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WO2014160947A1 - Inhibiteurs de diméthylarginine diméthylaminohydrolase et leurs procédés d'utilisation - Google Patents

Inhibiteurs de diméthylarginine diméthylaminohydrolase et leurs procédés d'utilisation Download PDF

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Publication number
WO2014160947A1
WO2014160947A1 PCT/US2014/032189 US2014032189W WO2014160947A1 WO 2014160947 A1 WO2014160947 A1 WO 2014160947A1 US 2014032189 W US2014032189 W US 2014032189W WO 2014160947 A1 WO2014160947 A1 WO 2014160947A1
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Prior art keywords
substituted
day
ddahi
administration
alkyl
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John P. Cooke
Yohannes T. Ghebremariam
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Leland Stanford Junior University
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Leland Stanford Junior University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/402—1-aryl substituted, e.g. piretanide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • Nitric oxide (NO) is a potent signaling molecule that needs to be tightly regulated to maintain metabolic and cardiovascular homeostasis.
  • the nitric oxide synthase (NOS)/ dimethylarginine dimethylaminohydrolase (DDAH)/ Asymmetric Dimethylarginine (ADMA) pathway is central to this regulation.
  • the small molecule ADMA competitively inhibits NOS, thus lowering NO levels.
  • the majority of ADMA is physiologically metabolized by DDAH, thus maintaining NO levels at physiological concentration.
  • NO synthesis and/or DDAH activity may be pathologically increased.
  • Such states include sepsis; fibrosis interstitial, e.g., pulmonary fibrosis; migraine headaches; and some inflammatory and autoimmune diseases.
  • the present disclosure provides DDAH inhibitors, and compositions, including pharmaceutical compositions, comprising the inhibitors.
  • DDAH inhibitors of the present disclosure are useful in treating disorders associated with excessive NO production and/or elevated DDAH activity.
  • the present disclosure provides methods of treating disorders associated with excessive NO production and/or elevated DDAH activity, the methods generally involving administering to an individual in need thereof an effective amount of a subject DDAH inhibitor.
  • the present disclosure provides a pharmaceutical formulation comprising a DDAH inhibitor of the formula:
  • Q 1 is N or CH
  • R 1 is selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl;
  • R 2 , R 3 , R 4 , and R 5 are independently selected from hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl; and
  • n is an integer from zero to four;
  • a formulation suitable for administration via any of a variety of routes of administration e.g., a formulation suitable for administration via inhalation, via oral administration, via intravenous administration, via buccal administration, via intranasal adminsitraiton, via subcutaneous administration, via transdermal administration, etc.
  • the present disclosure provides a pharmaceutical formulation comprising a DDAH inhibitor of the formula:
  • R 1 is selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl;
  • R 2 , R 3 , R 4 , and R 5 are independently selected from is selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl; and m is an integer from zero to four; and
  • a formulation suitable for administration via any of a variety of routes of administration e.g., a formulation suitable for administration via inhalation, via oral administration, via intravenous administration, via buccal administration, via intranasal adminsitraiton, via subcutaneous administration, via transdermal administration, etc.
  • the present disclosure provides a pharmaceutical formulation comprising a DDAH inhibitor of the formula:
  • R 1 is selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl;
  • R 2 , R 3 , R 4 , and R 5 are independently selected from is selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl; and m is an integer from zero to four; and
  • a formulation suitable for administration via any of a variety of routes of administration e.g., a formulation suitable for administration via inhalation, via oral administration, via intravenous administration, via buccal administration, via intranasal adminsitraiton, via subcutaneous administration, via transdermal administration, etc.
  • the DDAH inhibitor is selected from:
  • a subject pharmaceutical formulation e.g., a subject pharmaceutical formulation comprising a DDAH inhibitor of Formula la, lb, or Ic; or a DDAH inhibitor of Formula III; or a DDAH inhibitor of any one of Formulas II and IV-X
  • the DDAH inhibitor can be formulated with a fluid carrier and a propellant.
  • a subject pharmaceutical formulation e.g., a subject pharmaceutical formulation comprising a DDAH inhibitor of Formula la, lb, or Ic; or a DDAH inhibitor of Formula III; or a DDAH inhibitor of any one of Formulas II and IV-X
  • a subject pharmaceutical formulation e.g., a subject pharmaceutical formulation comprising a DDAH inhibitor of Formula la, lb, or Ic; or a DDAH inhibitor of Formula III; or a DDAH inhibitor of any one of Formulas II and IV-X
  • the DDAH inhibitor can be formulated with a fluid carrier and a propellant.
  • a subject pharmaceutical formulation e.g
  • the DDAH inhibitor can be in a dry powder formulation.
  • the DDAH inhibitor can be formulated for oral administration, for inhalational administration, for intravenous administration, for intranasal administration, for subcutaneous administration, for transdermal administration, for buccal administration, or for any other suitable route of administration.
  • the present disclosure provides a package for use in treating a disorder associated with excessive NO production and/or elevated DDAH activity, where the package comprises a container having therein a subject pharmaceutical formulation (e.g., a subject pharmaceutical formulation comprising a DDAH inhibitor of Formula la, lb, or Ic; or a DDAH inhibitor of Formula III; or a DDAH inhibitor of any one of Formulas II and IV-X).
  • a subject pharmaceutical formulation e.g., a subject pharmaceutical formulation comprising a DDAH inhibitor of Formula la, lb, or Ic; or a DDAH inhibitor of Formula III; or a DDAH inhibitor of any one of Formulas II and IV-X.
  • the package is a metered dose inhaler, and the DDAH inhibitor is formulated with a propellant.
  • the package is a dry powder inhaler, and the DDAH inhibitor is formulated in a dry powder formulation.
  • the package is a nebulizer, and the DDAH inhibitor is in an a
  • the present disclosure provides a metered dose inhaler having therein a subject pharmaceutical formulation, wherein the DDAH inhibitor is formulated with a propellant.
  • the present disclosure provides a dry powder inhaler having therein a subject pharmaceutical formulation, wherein the DDAH inhibitor is formulated in a dry powder formulation.
  • the present disclosure provides a nebulizer having therein a subject pharmaceutical formulation, wherein the DDAH inhibitor is in an aqueous or ethanolic solution.
  • the present disclosure provides an aerosol comprising a pharmaceutically active DDAH inhibitor.
  • the DDAH inhibitor is contained within aerosolized particles having a diameter in a range of from about 0.25 ⁇ to about 12 ⁇ .
  • the aerosol is in the form of a solution.
  • the aerosol is in the form of a suspension.
  • the aerosol is in the form of a powder.
  • the aerosol is in the form of a semi-solid preparation.
  • DDAH dimethylarginine dimethylaminohydrolase
  • Q 1 is S, O, NH or CH 2 ;
  • Q 2 is N or CH
  • Q 3 is N or CH
  • R 1 is selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl;
  • R 2 is selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl;
  • n is an integer from zero to four;
  • n is an integer from zero to three;
  • a formulation suitable for administration via any of a variety of routes of administration e.g., a formulation suitable for administration via inhalation, via oral administration, via intravenous administration, via buccal administration, via intranasal adminsitraiton, via subcutaneous administration, via transdermal administration, etc.
  • the DDAH inhibitor is:
  • the DDAH inhibitor of Formula III is formulated with a fluid carrier and a propellant; or the DDAH inhibitor of Formula III is in a dry powder formulation.
  • the present disclosure provides a package for use in treating a disorder associated with excessive NO production and/or elevated DDAH activity, the package comprising a container having therein a subject pharmaceutical formulation comprising a DDAH inhibitor of Formula III.
  • the package is a metered dose inhaler, and the DDAH inhibitor is formulated with a propellant; or the package is a dry powder inhaler, and the DDAH inhibitor is formulated in a dry powder formulation; or the package is a nebulizer, and the DDAH inhibitor is in an aqueous or ethanolic solution.
  • DDAH dimethylarginine dimethylaminohydrolase
  • R 1 is selected from hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocyclyl, and substituted heterocyclyl;
  • R 2 is selected from hydrogen, alkyl, and substituted alkyl
  • R 3 and R 4 are independently selected from is selected from hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl; and a pharmaceutically acceptable excipient.
  • a DDAH inhibitor of Formula Ila can be present in a formulation suitable for administration via any of a variety of routes of administration, e.g., a formulation suitable for administration via inhalation, via oral administration, via intravenous administration, via buccal administration, via intranasal adminsitraiton, via subcutaneous administration, via transdermal administration, etc.
  • the present disclosure provides a pharmaceutical formulation comprising a dimethylarginine dimethyl the formula:
  • R 1 is selected from hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocyclyl, and substituted heterocyclyl;
  • R 2 is selected from hydrogen, alkyl, and substituted alkyl
  • a compound of Formula lib can be present in a formulation suitable for administration via any of a variety of routes of administration, e.g., a formulation suitable for administration via inhalation, via oral administration, via intravenous administration, via buccal administration, via intranasal adminsitraiton, via subcutaneous administration, via transdermal administration, etc.
  • the DDAH inhibitor is selected from:
  • a subject pharmaceutical formulation e.g., a pharmaceutical formulation comprising a DDAH inhibitor of Formula Ila or Formula lib, or any of the above-listed specific DDAH inhibitors of Formula Ila or lib
  • the DDAH inhibitor is formulated with a fluid carrier and a propellant.
  • the DDAH inhibitor is in a dry powder formulation.
  • the present disclosure provides a package for use in treating a disorder associated with excessive NO production and/or elevated DDAH activity, the package comprising a container having therein a subject pharmaceutical formulation (e.g., a pharmaceutical formulation comprising a DDAH inhibitor of Formula Ila or Formula lib, or any of the above -listed specific DDAH inhibitors of Formula Ila or lib).
  • a subject pharmaceutical formulation e.g., a pharmaceutical formulation comprising a DDAH inhibitor of Formula Ila or Formula lib, or any of the above -listed specific DDAH inhibitors of Formula Ila or lib.
  • the package is a metered dose inhaler, and the DDAH inhibitor is formulated with a propellant.
  • the package is a dry powder inhaler, and the DDAH inhibitor is formulated in a dry powder formulation.
  • the package is a nebulizer, and the DDAH inhibitor is in an aqueous or ethanolic solution.
  • the present disclosure provides a method of treating an individual suffering from a disorder characterized by excessive NO production and/or elevated DDAH activity, the method comprising administering to the individual an effective amount of a subject pharmaceutical formulation, e.g., a pharmaceutical formulation comprising a DDAH inhibitor of any one of Formulas I-X, where the pharmaceutical formulation is administered via oral administration, via an inhalational route of administration, via intravenous administration, via buccal administration, via intranasal administration, via subcutaneous administration, via subcutaneous administration, via transdermal administration, or any other suitable route of administration.
  • a subject pharmaceutical formulation e.g., a pharmaceutical formulation comprising a DDAH inhibitor of any one of Formulas I-X
  • the pharmaceutical formulation is administered via oral administration, via an inhalational route of administration, via intravenous administration, via buccal administration, via intranasal administration, via subcutaneous administration, via subcutaneous administration, via transdermal administration, or any other suitable route of administration.
  • the present disclosure provides a method of treating an individual suffering from a disorder characterized by excessive NO production and/or elevated DDAH activity, the method comprising administering to the individual an effective amount of a subject pharmaceutical formulation.
  • the pharmaceutical formulation comprises a DDAH inhibitor of Formula Ila, lib, a compound of any of Formulas IV-IX, or a compound of Formula X
  • the formulation is administered by injection.
  • the pharmaceutical formulation comprises a DDAH inhibitor of Formula Ila, lib, a compound of any of Formulas IV-IX, or a compound of Formula X
  • the formulation administered with a carrier in the form of normal saline solution.
  • the DDAH inhibitor is administered locally to the airways of the patient.
  • the DDAH inhibitor is administered by inhalation.
  • the DDAH inhibitor is administered by insufflating an aerosol comprising the DDAH inhibitor.
  • the DDAH inhibitor is in a dry powder formulation.
  • the DDAH inhibitor is administered using a nebulizer.
  • the DDAH inhibitor is in an aqueous or ethanolic solution.
  • the individual being treated is a human.
  • the individual being treated is a non-human mammal.
  • the disease being treated is fibrosis.
  • the disease being treated is pulmonary fibrosis, e.g., IPF.
  • the present disclosure provides an in vitro method of identifying an agent that inhibits enzymatic activity of a DDAH polypeptide, the method comprising: a) contacting the DDAH polypeptide and a DDAH substrate with a test agent; and b) determining the effect, if any, of the test agent on DDAH enzymatic activity, wherein the substrate is asymmetric dimethylarginine, and the determining step is a colorimetric assay for L-citrulline.
  • a test agent that decreases DDAH activity, compare to a control, is an agent that inhibits DDAH activity.
  • an agent that inhibits DDAH activity can be considered a candidate agent for treating a disorder characterized by excessive NO production and/or elevated DDAH activity levels.
  • the substrate is ADMA
  • said determining step comprises reacting L-citrulline with 2,3-Dimethyl-l-phenyl-3-pyrazolin-5-one and 2,3-butanedione oxime.
  • the present disclosure provides a method of treating an individual having a disorder characterized by excessive NO production and/or elevated dimethylarginine dimethylaminohydrolase (DDAH) activity, the method comprising administering to the individual an effective amount of a DDAH inhibitor (DDAHi).
  • DDAH dimethylarginine dimethylaminohydrolase
  • the DDAHi is a compound of any one of Formulas I-X.
  • the DDAHi is a compound of Formula I.
  • the DDAHi can be Omeprazole, Lansoprazole, Esomeprazole, Rabeprazole, Pantoprazole, or
  • the DDAHi is a compound of one of Formulas II-X.
  • the DDAHi can be administered by a route selected from one or more of oral, inhalational, intravenous, subcutaneous, intranasal, buccal, intramuscular, and transdermal.
  • the DDAHi can be administered in an amount that provides for a concentration in blood of the DDAHi, within 24 hours to 48 hours of administration of the DDAHi, in the range of from about 1 ⁇ to about 100 ⁇ .
  • the DDAHi can be administered in an amount that provides for a concentration in blood of the DDAHi, within 24 hours to 48 hours of administration of the DDAHi, that is greater than 3 ⁇ . In any of the embodiments of a subject method, the DDAHi can be administered in an amount that provides for a sustained tissue concentration in the range of from about 3 ⁇ to about 100 ⁇ . In any of the embodiments of a subject method, the DDAHi can be administered in an amount that provides for an area under the curve of greater than about 2 ⁇ -hr/L when administered via oral administration.
  • the DDAHi can be administered in an amount that provides for an area under the curve of greater than about 2 ⁇ -hr/L when administered via intravenous administration. In any of the embodiments of a subject method, the DDAHi can be administered in an amount that provides for an area under the curve of greater than about 2 ⁇ -hr/L when administered via an inhalational route administration.
  • the disorder is fibrosis. In some cases, the disorder is pulmonary fibrosis. In some cases, the disorder is idiopathic pulmonary fibrosis (IPF).
  • the DDAHi is formulated to protect the pro-drug form of the compound from conversion by gastric fluid to a sulfenic acid form.
  • the method can further comprise administering at least a second therapeutic agent and/or carrying out at least a second therapy to treat the IPF.
  • said administering is via at least two different routes of administration, e.g., where the at least two different routes of administration include oral and inhalational routes of administration; or where the at least two different routes of administration include oral and intravenous routes of administration.
  • the present disclosure provides a pharmaceutical formulation comprising a DDAH inhibitor (DDAHi) of one of Formulas I-X in an amount of from about 10 mg to about 50 mg, from 50 mg to about 100 mg, or from about 100 mg to about 500 mg per unit dosage form.
  • the formulation comprises a second therapeutic agent.
  • suitable second therapeutic agent is selected from cyclophosphamide, azathioprine, N-acetylcysteine and pirfenidone.
  • the DDAHi can be a compound of Formula I.
  • the DDAHi can be Omeprazole, Lansoprazole, Esomeprazole, Rabeprazole, Pantoprazole, or Tenatoprazole. In any of the embodiments of a subject pharmaceutical formulation, the DDAHi can be formulated to protect the pro-drug form of the compound from conversion by gastric fluid to a sulfenic acid form. In any of the embodiments of a subject pharmaceutical formulation, the DDAHi can be formulated with an enteric coating.
  • the present disclosure provides a method of treating idiopathic pulmonary fibrosis in an individual, the method comprising administering to the individual an effective amount of a
  • the DDAHi is a compound of Formula la, Formula lb, or Formula Ic.
  • the DDAHi is Omeprazole, Lansoprazole, Esomeprazole, Rabeprazole, Pantoprazole, or Tenatoprazole.
  • the DDAHi can be administered by a route selected from one or more of oral, inhalational, intravenous, subcutaneous, intranasal, buccal, intramuscular, and transdermal.
  • the DDAHi can be administered in an amount that provides for a concentration in blood of the DDAHi, within 24 hours to 48 hours of administration of the DDAHi, in the range of from about 1 ⁇ to about 100 ⁇ . In any of the embodiments of a subject method of treating IPF, the DDAHi can be administered in an amount that provides for a concentration in blood of the DDAHi, within 24 hours to 48 hours of administration of the DDAHi, that is greater than 3 ⁇ . In any of the embodiments of a subject method of treating IPF, the DDAHi can be administered in an amount that provides for a sustained tissue concentration in the range of from about 3 ⁇ to about 100 ⁇ .
  • the DDAHi can be administered in an amount that provides for an area under the curve of greater than about 2 ⁇ - hr/L when administered via oral administration. In any of the embodiments of a subject method of treating IPF, the DDAHi can be administered in an amount that provides for an area under the curve of greater than about 2 ⁇ -hr/L when administered via intravenous administration. In any of the embodiments of a subject method of treating IPF, the DDAHi can be administered in an amount that provides for an area under the curve of greater than about 2 ⁇ -hr/L when administered via an inhalational route administration.
  • the DDAHi can be formulated to protect the pro-drug form of the compound from conversion by gastric fluid to a sulfenic acid form.
  • the method can further comprise administering at least a second therapeutic agent and/or carrying out at least a second therapy to treat the IPF.
  • administering a compound of Formula I can be carried out via at least two different routes of administration; e.g., where the at least two different routes of administration include oral and inhalational routes of administration; or where the at least two different routes of administration include oral and intravenous routes of administration.
  • Figure 1 provides graphs showing inhibition of DDAH activity by various compounds.
  • Figure 2 is a graph showing re-validation of proton pump inhibitors (PPIs) as DDAH inhibitors using CPM assay.
  • PPIs proton pump inhibitors
  • Figure 3 is a graph showing an orthogonal assay to validate PPIs as DDAH inhibitors.
  • Figure 4 is a graph showing production of L-citrulline from ADMA as a result of
  • Figure 5 is a graph that shows concentration of intracellular ADMA as a result of
  • Figure 6 is a graph showing direct inhibition of DDAH activity by small molecule PD 404.
  • Figure 7 is a graph showing re-validation of PD 404 as a DDAH inhibitor using CPM assay.
  • Figure 8 is a graph showing an orthogonal assay to validate PD 404 as a DDAH inhibitor.
  • Figure 9 is a graph showing production of L-citrulline from ADMA as a result of
  • Figure 10 shows a Western blot analysis showing the production of GST-DDAH (56.5kDa).
  • Figure 11A shows SDS-PAGE analysis of purified human DDAH1.
  • Figure 11B shows Western blot showing purified (after GST cleavage) recombinant human DDAH1 (-37 kDa).
  • Figure 12 shows a citrulline assay showing that the conversion of ADMA to L-citrulline by DDAH1 is proportional to time, temperature and enzyme concentration.
  • Figure 13 shows measurement of L-citrulline from primary human endothelial cell lysate.
  • Figure 14A-D show curve fit data showing inhibition of human DDAH-1 activity by selected small molecules using the CPM assay.
  • Figure 15 provides an amino acid sequence of a DDAH polypeptide.
  • Figure 16 depicts the NO/ADMA/DDAH pathway.
  • DMA dimethylamine
  • ADMA asymmetric dimethylarginine
  • SDMA symmetric dimethyl arginine
  • L-NMMA monomethyl arginine
  • PRMTs protein arginine methyltransferases
  • NO nitric oxide
  • NCE new chemical entity.
  • Figure 17 shows curve fit data showing inhibition of DDAH activity by a compound of Formula X.
  • Figure 18 depicts the effect of a proton pump inhibitor on collagen production by lung fibroblasts from patients with late-stage idiopathic pulmonary fibrosis.
  • Figure 19 depicts the effect of PPIs on lung alveolar epithelial cell proliferation.
  • Figure 20 depicts reversible inhibition of DDAH by PPIs.
  • Figure 21 is a graph showing the effect of PPI (Omeprazole) on cellular ADMA.
  • Figure 22 is a graph showing the effect of PPI on nitric oxide production.
  • Figure 23 depicts the effect of a proton pump inhibitor on collagen production by lung fibroblasts from patients with idiopathic pulmonary fibrosis (IPF).
  • IPF idiopathic pulmonary fibrosis
  • Figure 24 is a graph showing the effect of PPI on human lung alveolar epithelial cell proliferation.
  • Figure 25 is a graph showing the effect of PPI on mouse lung alveolar epithelial cell proliferation.
  • Figure 26 is a graph showing the effect of PPI on apoptosis in an Endoplasmic Reticulum (ER)- stressed human alveolar epithelial cell-line (A-549).
  • ER Endoplasmic Reticulum
  • Figure 27 is a graph showing an in vitro toxicology test of human alveolar epithelial cell-line (A-549) tested with PPIs.
  • Figure 28 is a graph showing an in vitro toxicology test of mouse alveolar epithelial cell-line (A-549) tested with PPIs.
  • Figure 29 depicts PPI-mediated reduction of iNOS protein levels in lung cells.
  • Figure 30 depicts upregulated gene expression of HOI in Early IPF Fibroblasts following PPI treatment.
  • Figure 31 depicts upregulated gene expression of HOI in Late IPF Fibroblasts following PPI treatment.
  • Figures 32-37 depict downregulated gene expression of various integrins in IPF fibroblasts following PPI treatment.
  • Figures 38-40 depict downregulated gene expression of various TGF-beta family members in IPF fibroblasts following PPI treatment.
  • Figures 41-46 depict downregulated gene expression of various BMP family members in IPF fibroblasts following PPI treatment.
  • Figure 47 depicts downregulated gene expression of SMAD6 in IPF fibroblasts following PPI treatment.
  • Figure 48 depicts downregulated gene expression of MMP8 in IPF fibroblasts following PPI treatment.
  • Figure 49 depicts upregulated gene expression of HOI in COPD fibroblasts following PPI treatment.
  • Figure 50 depicts upregulated gene expression of HOI in COPD bronchial epithelial cells following PPI treatment.
  • Figure 51 depicts downregulated gene expression of TNF-alpha in COPD bronchial epithelial cells following PPI treatment.
  • Figure 52 depicts downregulated gene expression of TRPVl in COPD bronchial epithelial cells following PPI treatment.
  • Alkyl refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 10 carbon atoms, e.g., from 1 to 6 carbon atoms. This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH 3 -), ethyl (CH 3 CH 2 -), n-propyl (CH 3 CH 2 CH 2 -), isopropyl ((CH 3 ) 2 CH-), n-butyl (CH 3 CH 2 CH 2 CH 2 -), isobutyl ((CH 3 ) 2 CHCH 2 -), sec-butyl
  • substituted alkyl refers to an alkyl group as defined herein wherein one or more carbon atoms in the alkyl chain have been optionally replaced with a heteroatom such as -0-, -N-, -S-, - S(0) n - (where n is 0 to 2), -NR- (where R is hydrogen or alkyl) and having from 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheter
  • Alkylene refers to divalent aliphatic hydrocarbyl groups, e.g., having from 1 to 6 carbon atoms or from 1 to 3 carbon atoms that are either straight-chained or branched, and which are optionally interrupted with one or more groups selected from -0-, -NR 10 -, -NR 10 C(O)-, -C(0)NR 10 - and the like. This term includes, by way of example, methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), n-propylene
  • Substituted alkylene refers to an alkylene group having from 1 to 3 hydrogens replaced with substituents as described for carbons in the definition of "substituted” below.
  • alkane refers to alkyl group and alkylene group, as defined herein.
  • alkylaminoalkyl refers to the groups R NHR - where R is alkyl group as defined herein and R is alkylene, alkenylene or alkynylene group as defined herein.
  • alkaryl or “aralkyl” refers to the groups -alkylene-aryl and -substituted alkylene-aryl where alkylene, substituted alkylene and aryl are defined herein.
  • Alkoxy refers to the group -O-alkyl, wherein alkyl is as defined herein. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, n-pentoxy, and the like.
  • alkoxy also refers to the groups alkenyl-O-, cycloalkyl-O-, cycloalkenyl-O-, and alkynyl-O-, where alkenyl, cycloalkyl, cycloalkenyl, and alkynyl are as defined herein.
  • substituted alkoxy refers to the groups substituted alkyl-O-, substituted alkenyl- 0-, substituted cycloalkyl-O-, substituted cycloalkenyl-O-, and substituted alkynyl-O- where substituted alkyl, substituted alkenyl, substituted cycloalkyl, substituted cycloalkenyl and substituted alkynyl are as defined herein.
  • alkoxyamino refers to the group -NH-alkoxy, wherein alkoxy is defined herein.
  • haloalkoxy refers to the groups alkyl-O- wherein one or more hydrogen atoms on the alkyl group have been substituted with a halo group and include, by way of examples, groups such as trifluoromethoxy, and the like.
  • haloalkyl refers to a substituted alkyl group as described above, wherein one or more hydrogen atoms on the alkyl group have been substituted with a halo group.
  • groups include, without limitation, fluoroalkyl groups, such as trifluoromethyl, difluoromethyl, trifluoroethyl and the like.
  • alkylalkoxy refers to the groups -alkylene-O-alkyl, alkylene-O-substituted alkyl, substituted alkylene-O-alkyl, and substituted alkylene-O-substituted alkyl wherein alkyl, substituted alkyl, alkylene and substituted alkylene are as defined herein.
  • alkylthioalkoxy refers to the group -alkylene-S-alkyl, alkylene-S-substituted alkyl, substituted alkylene-S-alkyl and substituted alkylene-S-substituted alkyl wherein alkyl, substituted alkyl, alkylene and substituted alkylene are as defined herein.
  • Alkenyl refers to straight chain or branched hydrocarbyl groups having from 2 to 6 carbon atoms or from 2 to 4 carbon atoms, and having at least 1 site of double bond unsaturatio, e.g., from 1 to 2 sites of double bond unsaturation.
  • This term includes, by way of example, bi-vinyl, allyl, and but-3-en-l-yl. Included within this term are the cis and trans isomers or mixtures of these isomers.
  • substituted alkenyl refers to an alkenyl group as defined herein having from 1 to 5 substituents, or from 1 to 3 substituents, selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxy
  • Alkynyl refers to straight or branched monovalent hydrocarbyl groups having from 2 to 6 carbon atoms or from 2 to 3 carbon atoms and having at least 1 site of triple bond unsaturation, e.g., from 1 to 2 sites of triple bond unsaturation.
  • alkynyl groups include acetylenyl (-C ⁇ CH), and propargyl (-CH 2 C ⁇ CH).
  • substituted alkynyl refers to an alkynyl group as defined herein having from 1 to 5 substituents, or from 1 to 3 substituents, selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, al
  • Alkynyloxy refers to the group -O-alkynyl, wherein alkynyl is as defined herein.
  • Alkynyloxy includes, by way of example, ethynyloxy, propynyloxy, and the like.
  • Acyl refers to the groups H-C(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C(O)-, substituted alkenyl-C(O)-, alkynyl-C(O)-, substituted alkynyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, cycloalkenyl-C(O)-, substituted cycloalkenyl-C(O)-, aryl-C(O)-, substituted aryl-C(O)-, heteroaryl-C(O)-, substituted heteroaryl-C(O)-, heterocyclyl-C(O)-, and substituted heterocyclyl-C(O)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkenyl-C
  • Acylamino refers to the groups -NR 20 C(O)alkyl, -NR 20 C(O)substituted alkyl, N
  • R 20 C(O)cycloalkyl, -NR 20 C(O)substituted cycloalkyl, -NR 20 C(O)cycloalkenyl, -NR 20 C(O)substituted cycloalkenyl, -NR 20 C(O)alkenyl, -NR 20 C(O)substituted alkenyl, -NR 20 C(O)alkynyl, - NR 20 C(O)substituted alkynyl, -NR 20 C(O)aryl, -NR 20 C(O)substituted aryl, -NR 20 C(O)heteroaryl, -NR 20 C(O)substituted heteroaryl, -NR 20 C(O)heterocyclic, and -NR 20 C(O)substituted heterocyclic, wherein R 20 is hydrogen or alkyl and wherein alkyl, substituted alkyl, alkenyl, substituted
  • Aminocarbonyl or the term “aminoacyl” refers to the group -C(0)NR 21 R 22 , wherein R 21 and R 22 independently are selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 21 and R 22 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycl
  • Aminocarbonylamino refers to the group -NR 21 C(0)NR 22 R 23 where R 21 , R 22 , and R 23 are independently selected from hydrogen, alkyl, aryl or cycloalkyl, or where two R groups are joined to form a heterocyclyl group.
  • alkoxycarbonylamino refers to the group -NRC(0)OR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclyl wherein alkyl, substituted alkyl, aryl, heteroaryl, and heterocyclyl are as defined herein.
  • acyloxy refers to the groups alkyl-C(0)0-, substituted alkyl-C(0)0-, cycloalkyl-C(0)0-, substituted cycloalkyl-C(0)0-, aryl-C(0)0-, heteroaryl-C(0)0-, and heterocyclyl- C(0)0- wherein alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, and heterocyclyl are as defined herein.
  • Aminosulfonyl refers to the group -S0 2 NR 21 R 22 , wherein R 21 and R 22 independently are selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and where R 21 and R 22 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group and alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl
  • Sulfonylamino refers to the group -NR 21 S0 2 R 22 , wherein R 21 and R 22 independently are selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 21 and R 22 are optionally joined together with the atoms bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, substituted cycl
  • Aryl or “Ar” refers to a monovalent aromatic carbocyclic group of from 6 to 18 carbon atoms having a single ring (such as is present in a phenyl group) or a ring system having multiple condensed rings (examples of such aromatic ring systems include naphthyl, anthryl and indanyl) which condensed rings may or may not be aromatic, provided that the point of attachment is through an atom of an aromatic ring. This term includes, by way of example, phenyl and naphthyl.
  • such aryl groups can optionally be substituted with from 1 to 5 substituents, or from 1 to 3 substituents, selected from acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halogen, nitro, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thi
  • Aryloxy refers to the group -O-aryl, wherein aryl is as defined herein, including, by way of example, phenoxy, naphthoxy, and the like, including optionally substituted aryl groups as also defined herein.
  • Amino refers to the group -NH 2 .
  • substituted amino refers to the group -NRR where each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, and heterocyclyl provided that at least one R is not hydrogen.
  • azido refers to the group -N 3 .
  • Carboxyl refers to -C0 2 H or salts thereof.
  • Carboxyl ester or “carboxy ester” or the terms “carboxyalkyl” or “carboxylalkyl” refers to the groups -C(0)0-alkyl, -C(0)0-substituted alkyl, -C(0)0-alkenyl, -C(0)0-substituted alkenyl, -C(0)0-alkynyl, -C(0)0-substituted alkynyl, -C(0)0-aryl, -C(0)0-substituted aryl,
  • alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
  • alkyl -0-C(0)0-substituted alkyl, -0-C(0)0-alkenyl, -0-C(0)0-substituted alkenyl, -0-C(0)0-alkynyl, -0-C(0)0-substituted alkynyl, -0-C(0)0-aryl, -0-C(0)0-substituted aryl, -0-C(0)0-cycloalkyl, -O- C(0)0-substituted cycloalkyl, -0-C(0)0-cycloalkenyl, -0-C(0)0-substituted cycloalkenyl, -0-C(0)0- heteroaryl, -0-C(0)0-substituted heteroaryl, -0-C(0)0-heterocyclic, and -0-C(0)0-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycl
  • Cycloalkyl refers to cyclic alkyl groups of from 3 to 10 carbon atoms having single or multiple cyclic rings including fused, bridged, and spiro ring systems.
  • suitable cycloalkyl groups include, for instance, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl and the like.
  • Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, and the like.
  • substituted cycloalkyl refers to cycloalkyl groups having from 1 to 5 substituents, or from 1 to 3 substituents, selected from alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy,
  • Cycloalkenyl refers to non-aromatic cyclic alkyl groups of from 3 to 10 carbon atoms having single or multiple rings and having at least one double bond, e.g., from 1 to 2 double bonds.
  • substituted cycloalkenyl refers to cycloalkenyl groups having from 1 to 5 substituents, or from 1 to 3 substituents, selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamin
  • Cycloalkynyl refers to non-aromatic cycloalkyl groups of from 5 to 10 carbon atoms having single or multiple rings and having at least one triple bond.
  • Cycloalkoxy refers to -O-cycloalkyl
  • Cycloalkenyloxy refers to -O-cycloalkenyl.
  • Halo or "halogen” refers to fluoro, chloro, bromo, and iodo.
  • Heteroaryl refers to an aromatic group of from 1 to 15 carbon atoms, such as from 1 to
  • heteroaryl groups can have a single ring (such as, pyridinyl, imidazolyl or furyl) or multiple condensed rings in a ring system (for example as in groups such as, indolizinyl, quinolinyl, benzofuran, benzimidazolyl or benzothienyl), wherein at least one ring within the ring system is aromatic and at least one ring within the ring system is aromatic , provided that the point of attachment is through an atom of an aromatic ring.
  • the nitrogen and/or sulfur ring atom(s) of the heteroaryl group are optionally oxidized to provide for the N-oxide (N ⁇ 0), sulfinyl, or sulfonyl moieties.
  • This term includes, by way of example, pyridinyl, pyrrolyl, indolyl, thiophenyl, and furanyl.
  • heteroaryl groups can be optionally substituted with 1 to 5 substituents, or from 1 to 3 substituents, selected from acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halogen, nitro, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thio
  • heteroaryl refers to the groups -alkylene -heteroaryl where alkylene and heteroaryl are defined herein. This term includes, by way of example, pyridylmethyl, pyridylethyl, indolylmethyl, and the like.
  • Heteroaryloxy refers to -O-heteroaryl.
  • Heterocycle refers to a saturated or unsaturated group having a single ring or multiple condensed rings, including fused bridged and spiro ring systems, and having from 3 to 20 ring atoms, including 1 to 10 hetero atoms.
  • These ring atoms are selected from the group consisting of nitrogen, sulfur, or oxygen, wherein, in fused ring systems, one or more of the rings can be cycloalkyl, aryl, or heteroaryl, provided that the point of attachment is through the non-aromatic ring.
  • the nitrogen and/or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for the N-oxide, -S(O)-, or -S0 2 - moieties.
  • heterocycles and heteroaryls include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline,
  • heterocyclic groups can be optionally substituted with 1 to 5, or from 1 to 3 substituents, selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino,
  • Heterocyclyloxy refers to the group -O-heterocyclyl.
  • heterocyclylthio refers to the group heterocyclic-S-.
  • heterocyclene refers to the diradical group formed from a heterocycle, as defined herein.
  • hydroxyamino refers to the group -NHOH.
  • Neitro refers to the group -N0 2 .
  • Sulfonyl refers to the group S0 2 -alkyl, S0 2 -substituted alkyl, S0 2 -alkenyl, S0 2 - substituted alkenyl, S0 2 -cycloalkyl, S0 2 -substituted cylcoalkyl, S0 2 -cycloalkenyl, S0 2 -substituted cylcoalkenyl, S0 2 -aryl, S0 2 -substituted aryl, S0 2 -heteroaryl, S0 2 -substituted heteroaryl, S0 2 - heterocyclic, and S0 2 -substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkeny
  • Sulfonyloxy refers to the group -OS0 2 -alkyl, OS0 2 -substituted alkyl, OS0 2 -alkenyl, OS0 2 -substituted alkenyl, OS0 2 -cycloalkyl, OS0 2 -substituted cylcoalkyl, OS0 2 -cycloalkenyl, OS0 2 -substituted cylcoalkenyl, OS0 2 -aryl, OS0 2 -substituted aryl, OS0 2 -heteroaryl, OS0 2 - substituted heteroaryl, OS0 2 -heterocyclic, and OS0 2 substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkeny
  • aminocarbonyloxy refers to the group -OC(0)NRR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
  • Alkylthio or the term “thioalkoxy” refers to the group -S-alkyl, wherein alkyl is as defined herein.
  • sulfur may be oxidized to -S(O)-.
  • the sulfoxide may exist as one or more stereoisomers.
  • substituted thioalkoxy refers to the group -S-substituted alkyl.
  • thioaryloxy refers to the group aryl-S- wherein the aryl group is as defined herein including optionally substituted aryl groups also defined herein.
  • thioheteroaryloxy refers to the group heteroaryl-S- wherein the heteroaryl group is as defined herein including optionally substituted aryl groups as also defined herein.
  • heterocyclooxy refers to the group heterocyclyl-S- wherein the heterocyclyl group is as defined herein including optionally substituted heterocyclyl groups as also defined herein.
  • substituted when used to modify a specified group or radical, can also mean that one or more hydrogen atoms of the specified group or radical are each, independently of one another, replaced with the same or different substituent groups as defined below.
  • -OS0 2 OR 70 -P(0)(0 ) 2 (M + ) 2 , -P(O)(OR 70 )O ⁇ M + , -P(0)(OR 70 ) 2 , -C(0)R 70 , -C(S)R 70 , -C(NR 70 )R 70 , -C(0)OTVI + , -C(0)OR 70 , -C(S)OR 70 , -C(O)NR 80 R 80 , -C(NR 70 )NR 80 R 80 , -C(NR 70 )NR 80 R 80 , -OC(0)R 70 , -OC(S)R 70 , -OC(0)0 " M + , -OC(0)OR 70 , -OC(S)OR 70 , -NR 70 C(O)R 70 , -NR 70 C(S)R 70 , -NR 70 CO 2 TVI + , -NR 70 CO 2 R 70 , -NR 70 C(S)OR 70 ,
  • Each M + may independently be, for example, an alkali ion, such as K + , Na + , Li + ; an ammonium ion, such as + N(R 60 ) 4 ; or an alkaline earth ion, such as [Ca 2+ ] 0 .5, [Mg 2+ ]o.5, or [Ba 2+ ]o.5
  • subscript 0.5 means that one of the counter ions for such divalent alkali earth ions can be an ionized form of a compound of the invention and the other a typical counter ion such as chloride, or two ionized compounds disclosed herein can serve as counter ions for such divalent alkali earth ions, or a doubly ionized compound of the invention can serve as the counter ion for such divalent alkali earth ions).
  • -NR 80 R 80 is meant to include -NH 2 , -NH-alkyl, N-pyrrolidinyl, N-piperazinyl, 4N-methyl-piperazin-l -yl and N-morpholinyl.
  • substituent groups for hydrogens on unsaturated carbon atoms in "substituted" alkene, alkyne, aryl and heteroaryl groups are, unless otherwise specified, -R 60 , halo, -O M + , -OR 70 , -SR 70 , -S ⁇ M + , -NR 80 R 80 , trihalomethyl, -CF 3 , -CN, -OCN, -SCN, -NO, -N0 2 , -N 3 , -S0 2 R 70 , -S0 3 ⁇ M + , -S0 3 R 70 , -OS0 2 R 70 , -OS0 3 ⁇ M + , -OS0 3 R 70 , -P0 3 "2 (M + ) 2 , -P(O)(OR 70 )O ⁇ M + , -P(O)(OR 70 ) 2 , -C(0)
  • substituent groups for hydrogens on nitrogen atoms in "substituted" heteroalkyl and cycloheteroalkyl groups are, unless otherwise specified, -R 60 , -0 " M + , -OR 70 , -SR 70 , -S " M + , -NR 80 R 80 , trihalomethyl, -CF 3 , -CN, -NO, -NO* -S(0) 2 R 70 , -S(0) 2 O M + , -S(0) 2 OR 70 , -OS(0) 2 R 70 , -OS(0) 2 O M + , -OS(0) 2 OR 70 , -P(0)(0 ) 2 (M + ) 2 , -P(O)(OR 70 )O " M + , -P(O)(OR 70 )(OR 70 ), -C(0)R 70 , -C(S)R 70 , -C(NR 70 ),
  • a group that is substituted has 1, 2, 3, or 4 substituents, 1, 2, or 3 substituents, 1 or 2 substituents, or 1 substituent.
  • any of the groups disclosed herein which contain one or more substituents it is understood, of course, that such groups do not contain any substitution or substitution patterns which are sterically impractical and/or synthetically non-feasible.
  • the subject compounds include all stereochemical isomers arising from the substitution of these compounds.
  • salt means a salt which is acceptable for administration to a patient, such as a mammal (salts with counterions having acceptable mammalian safety for a given dosage regime).
  • Such salts can be derived from pharmaceutically acceptable inorganic or organic bases and from pharmaceutically acceptable inorganic or organic acids.
  • “Pharmaceutically acceptable salt” refers to pharmaceutically acceptable salts of a compound, which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, formate, tartrate, besylate, mesylate, acetate, maleate, oxalate, and the like.
  • salt thereof means a compound formed when a proton of an acid is replaced by a cation, such as a metal cation or an organic cation and the like.
  • the salt is a pharmaceutically acceptable salt, although this is not required for salts of intermediate compounds that are not intended for administration to a patient.
  • salts of the present compounds include those wherein the compound is protonated by an inorganic or organic acid to form a cation, with the conjugate base of the inorganic or organic acid as the anionic component of the salt.
  • solvent refers to a complex formed by combination of solvent molecules with molecules or ions of the solute.
  • the solvent can be an organic compound, an inorganic compound, or a mixture of both.
  • Some examples of solvents include, but are not limited to, methanol, N,N-dimethylformamide, tetrahydrofuran, dimethylsulf oxide, and water. When the solvent is water, the solvate formed is a hydrate.
  • Stereoisomers refer to compounds that have same atomic connectivity but different atomic arrangement in space. Stereoisomers include cis-trans isomers, E and Z isomers, enantiomers, and diastereomers.
  • pyrazoles imidazoles, benzimidazoles, triazoles, and tetrazoles.
  • a "pharmaceutical composition” is meant to encompass a composition suitable for administration to a subject, such as a mammal, especially a human.
  • a subject such as a mammal, especially a human.
  • a pharmaceutical composition suitable for administration to a subject, such as a mammal, especially a human.
  • compositions are sterile, and is free of contaminants that are capable of eliciting an undesirable response within the subject (e.g., the compound(s) in the pharmaceutical composition is pharmaceutical grade).
  • Pharmaceutical compositions can be designed for administration to subjects or patients in need thereof via a number of different routes of administration including oral, buccal, rectal, parenteral, intraperitoneal, intradermal, intratracheal, inhalational, and the like.
  • a subject composition is formulated with an excipient other than dimethylsulf oxide (DMSO).
  • DMSO dimethylsulf oxide
  • the pharmaceutical compositions are suitable for administration by a route other than transdermal administration.
  • a pharmaceutical composition will in some embodiments include a subject compound and a pharmaceutically acceptable excipient.
  • a pharmaceutically acceptable excipient is other than DMSO.
  • pharmaceutically acceptable derivatives of a compound of the invention include salts, esters, enol ethers, enol esters, acetals, ketals, orthoesters, hemiacetals, hemiketals, acids, bases, solvates, hydrates or prodrugs thereof. Such derivatives may be readily prepared by those of skill in this art using known methods for such derivatization. The compounds produced may be administered to animals or humans without substantial toxic effects and are either pharmaceutically active or are prodrugs.
  • “Pharmaceutically effective amount” and “therapeutically effective amount” refer to the amount of a compound that, when administered to a mammal or other subject for treating a disease, is sufficient to effect such treatment for the disease.
  • the “therapeutically effective amount” will vary depending on the compound or the cell, the disease and its severity and the age, weight, etc., of the subject to be treated.
  • co-administration and “in combination with” include the administration of two or more therapeutic agents either simultaneously, concurrently or sequentially within no specific time limits.
  • the agents are present in the cell or in the subject's body at the same time or exert their biological or therapeutic effect at the same time.
  • the therapeutic agents are in the same composition or unit dosage form. In other embodiments, the therapeutic agents are in separate compositions or unit dosage forms.
  • a first agent can be administered prior to (e.g., minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second therapeutic agent.
  • the terms "individual,” “subject,” “host,” and “patient,” used interchangeably herein, refer to a mammal, including, but not limited to, murines (rats, mice), non-human primates, humans, canines, felines, ungulates (e.g., equines, bovines, ovines, porcines, caprines), etc.
  • Fibrosis refers to a pathological condition resulting from an overproduction or aberrant production of fibrous tissue (e.g., fibrous connective tissue) in an organ or tissue, e.g., in a reparative or reactive process.
  • Fibrotic disorders include, but are not limited to, pulmonary fibrosis, including idiopathic pulmonary fibrosis (IPF) and pulmonary fibrosis from a known etiology;liver fibrosis; and renal fibrosis.
  • Other exemplary fibrotic conditions include musculoskeletal fibrosis, cardiac fibrosis, vascular fibrosis, post-surgical adhesions, scleroderma, glaucoma, and skin lesions such as keloids.
  • treating means the treating or treatment of a disease or medical condition in a patient, such as a mammal (e.g., a human) that includes: (a) preventing the disease or medical condition from occurring, such as, prophylactic treatment of a subject; (b) ameliorating the disease or medical condition, such as, eliminating or causing regression of the disease or medical condition in a patient; (c) suppressing the disease or medical condition, for example by, slowing or arresting the development of the disease or medical condition in a patient; or (d) alleviating a symptom of the disease or medical condition in a patient.
  • a mammal e.g., a human
  • the present disclosure provides DDAH modulators, e.g., DDAH inhibitors, and compositions, including pharmaceutical compositions comprising such inhibitors.
  • DDAH modulators e.g., DDAH inhibitors
  • compositions including pharmaceutical compositions comprising such inhibitors.
  • the present disclosure provides methods of treating an individual having a disorder characterized by excessive NO production and/or elevated DDAH activity, the method comprising administering to the individual an effective amount of a DDAH inhibitor (DDAHi) of any one of Formulas I-X.
  • DDAHi DDAH inhibitor
  • ADMA and monomethyl-L- arginine are endogenous competitive inhibitors of nitric oxide synthase (NOS). These methylarginines are generated by the methylation of arginine residues on histones and other proteins by a family of enzymes known as Protein Arginine Methyl Transferases (PRMTs). During the hydrolysis of proteins containing methylarginine residues, free ADMA and L-NMMA (monomethyl arginine) are released.
  • PRMTs Protein Arginine Methyl Transferases
  • the present disclosure provides small molecules and formulation that regulate NO by controlling the activity of DDAH. Pharmacological inhibition of DDAHl leads to higher ADMA levels and regulation of NO production.
  • a subject DDAH is useful for treating a patient suffering from a disorder characterized by excessive NO production, and/or elevated DDAH activity.
  • the present disclosure provides a method of treating a patient suffering from a disorder characterized by excessive NO production, and/or elevated DDAH activity, the method comprising administering to said patient an effective amount of a compound of formulae I-X.
  • the present disclosure also provides a pharmaceutical composition comprising a compound of the formulae I-X and a pharmaceutically acceptable excipient, wherein the compound is in a formulation suitable for delivery by an oral route of administration, by inhalation, by insufflation, or by any other suitable route of administration, or by two or more routes of
  • the present disclosure provides pharmaceutical compositions comprising a DDAH inhibitor and a pharmaceutically acceptable excipient, in a formulation suitable for administration by inhalation, e.g., inhalation into the lungs.
  • the present disclosure provides a pharmaceutical composition comprising a compound of any one of Formulae I-X, below, and a pharmaceutically acceptable excipient, where the compound is in a formulation suitable for delivery by inhalation.
  • Administration by inhalation can provide for smaller doses delivered locally to the specific cells in the lung which are most in need of treatment. By delivering smaller doses, any adverse side effects are eliminated or substantially reduced. By delivering directly to the cells which are most in need of treatment, the effect of the treatment will be realized more quickly.
  • a compound of Formulae I-X may be administered to the afflicted patient by means of a pharmaceutical delivery system for the inhalation route.
  • the compounds may be formulated in a form suitable for administration by inhalation.
  • the pharmaceutical delivery system is one that is suitable for respiratory therapy by administration via inhalation of a compound of any one of Formulae I-X thereof to lung tissue, e.g., the bronchi.
  • the pharmaceutical compositions of the embodiments can be prepared by thoroughly and intimately mixing or blending a compound of any one of Formulae I-X with a pharmaceutically acceptable carrier and one or more optional ingredients. If necessary or desired, the resulting uniformly blended mixture can then be shaped or loaded into tablets, capsules, pills, canisters, cartridges, dispensers and the like using conventional procedures and equipment.
  • the disclosure provides a system that depends on the power of a compressed gas to expel a compound of any one of Formulae I-X from a container.
  • An aerosol or pressurized package can be employed for this purpose.
  • aerosol is used in its conventional sense as referring to very fine liquid or solid particles carries by a propellant gas under pressure to a site of therapeutic application.
  • the aerosol contains the therapeutically active compound, which can be dissolved, suspended, or emulsified in a mixture of a fluid carrier and a propellant.
  • the aerosol can be in the form of a solution, suspension, emulsion, powder, or semi-solid preparation.
  • Aerosols employed in the present embodiments are intended for administration as fine, solid particles or as liquid mists via the respiratory tract of a patient.
  • Various types of propellants known to one of skill in the art can be utilized. Examples of suitable propellants include, but are not limited to, hydrocarbons or other suitable gas.
  • the dosage unit may be determined by providing a value to deliver a metered amount.
  • the pharmaceutical compositions are suitable for inhaled administration.
  • Suitable pharmaceutical compositions for inhaled administration will typically be in the form of an aerosol or a powder.
  • Such compositions are generally administered using well-known delivery devices, such as a nebulizer inhaler, a metered-dose inhaler (MDI), a dry powder inhaler (DPI) or a similar delivery device.
  • MDI metered-dose inhaler
  • DPI dry powder inhaler
  • a compound of any one of Formulae I-X is lyophilized.
  • a compound of any one of Formulae I-X is lyophilized; and is solubilized in a liquid solution (e.g., an aqueous solution; an ethanolic solution; etc.) just prior to use.
  • a compound of any one of Formulae I-X is lyophilized; and is solubilized in a liquid solution (e.g., an aqueous solution; an ethanolic solution; etc.) just prior to use via a nebulizer.
  • the pharmaceutical composition comprising the active agent is administered by inhalation using a nebulizer inhaler.
  • a nebulizer inhaler typically produce a stream of high velocity air that causes the pharmaceutical composition comprising the active agent to spray as a mist that is carried into the patient's respiratory tract.
  • the active agent is typically dissolved in a suitable carrier to form a solution.
  • the active agent can be micronized and combined with a suitable carrier to form a suspension of micronized particles of respirable size, where micronized is typically defined as having about 90% or more of the particles with a diameter of less than about 10 ⁇ .
  • suitable nebulizer devices are provided commercially, for example, by PARI GmbH (Starnberg, German).
  • Other nebulizer devices include Respimat (Boehringer Ingelheim) and those disclosed, for example, in U.S. Pat. No. 6,123,068 and WO 97/12687.
  • a representative pharmaceutical composition for use in a nebulizer inhaler comprises an isotonic aqueous solution comprising from about 0.05 ⁇ g/mL to about 10 mg/mL, or from about 10 mg/mL to about 50 mg/mL, of a compound of any one of Formulae I-X or a pharmaceutically acceptable salt or solvate or stereoisomer thereof.
  • the pharmaceutical composition comprising the active agent is administered by inhalation using a dry powder inhaler.
  • dry powder inhalers typically administer the active agent as a free -flowing powder that is dispersed in a patient's air-stream during inspiration.
  • the active agent is typically formulated with a suitable excipient such as lactose or starch.
  • a representative pharmaceutical composition for use in a dry powder inhaler comprises dry lactose having a particle size between about 1 ⁇ and about 100 ⁇ and micronized particles of a compound of any one of Formulae I-X, or a pharmaceutically acceptable salt or solvate or stereoisomer thereof.
  • Such a dry powder formulation can be made, for example, by combining the lactose with the active agent and then dry blending the components.
  • the active agent can be formulated without an excipient.
  • the pharmaceutical composition is then typically loaded into a dry powder dispenser, or into inhalation cartridges or capsules for use with a dry powder delivery device.
  • dry powder inhaler delivery devices include Diskhaler (GlaxoSmithKline, Research Triangle Park, N.C.) (see, e.g., U.S. Pat. No. 5,035,237); Diskus (GlaxoSmithKline) (see, e.g., U.S. Pat. No. 6,378,519; Turbuhaler (AstraZeneca, Wilmington, Del.) (see, e.g., U.S. Pat. No.
  • the pharmaceutical composition comprising an active agent is administered by inhalation using a metered-dose inhaler.
  • an active agent e.g., a compound of any one of Formulae I-X
  • metered-dose inhalers typically discharge a measured amount of the active agent or a
  • compositions administered using a metered-dose inhaler can comprise a solution or suspension of the active agent in a liquefied propellant.
  • a liquefied propellant may be employed including chlorofluorocarbons, such as CC1 3 F, and hydrofluoroalkanes (HFAs), such as 1,1,1,2-tetrafluoroethane (HFA 134a) and 1,1, 1,2,3,3, 3-heptafluoro-n-propane, (HFA 227). Due to concerns about
  • a representative pharmaceutical composition for use in a metered-dose inhaler comprises from about 0.01% to about 5% by weight of a compound of any one of Formulae I-X, or a
  • pharmaceutically acceptable salt or solvate or stereoisomer thereof from about 0% to about 20% by weight ethanol; and from about 0% to about 5% by weight surfactant; with the remainder being an HFA propellant.
  • compositions are typically prepared by adding chilled or pressurized
  • hydrofluoroalkane to a suitable container containing the active agent, ethanol (if present) and the surfactant (if present).
  • the active agent is micronized and then combined with the propellant.
  • the formulation is then loaded into an aerosol canister, which forms a portion of a metered-dose inhaler device. Examples of metered-dose inhaler devices developed specifically for use with HFA propellants are provided in U.S. Pat. Nos. 6,006,745 and 6,143,277.
  • a suspension formulation can be prepared by spray drying a coating of surfactant on micronized particles of the active agent. See, for example, WO 99/53901 and WO 00/61108.
  • any conventional carrier or excipient may be used in the pharmaceutical compositions of the embodiments.
  • the choice of a particular carrier or excipient, or combinations of carriers or excipients, will depend on the mode of administration being used to treat a particular patient or type of medical condition or disease state.
  • the preparation of a suitable pharmaceutical composition for a particular mode of administration is well within the scope of those skilled in the pharmaceutical arts.
  • the ingredients for such compositions are commercially available from, for example, Sigma, P.O. Box 14508, St. Louis, Mo. 63178.
  • conventional formulation techniques are described in Remington: The Science and Practice of
  • compositions which can serve as pharmaceutically acceptable carriers or excipients include, but are not limited to, the following: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar;
  • a subject pharmaceutical formulation suitable for inhalation comprises a DDAH inhibitor.
  • DDAH inhibitors suitable DDAH inhibitors.
  • a formula number is meant to encompass all forms of the formula number.
  • reference to formula (I) is meant to include compounds of formula (la), (lb), and (Ic).
  • the embodiments include pharmaceutical compositions formulated for inhalational de Formula la:
  • Q 1 is N or CH
  • R 1 is selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl;
  • R 2 , R 3 , R 4 , and R 5 are independently selected from hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl; and
  • n is an integer from zero to four;
  • the embodiments include pharmaceutical compositions formulated for inhalational deliver which compositions include a compound of Formula lb:
  • R 1 is selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl;
  • R 2 , R 3 , R 4 , and R 5 are independently selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl; and
  • n is an integer from zero to four;
  • compositions formulated for inhalational deliver which include a compound of Formula Ic:
  • R is selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl;
  • R 2 , R 3 , R 4 , and R 5 are independently selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl; and
  • n is an integer from zero to four;
  • Q 1 is N or CH. In certain embodiments, Q 1 is N. In certain embodiments,
  • R 1 is selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl.
  • R 1 is alkyl or substituted alkyl. In certain embodiments, R 1 is hydroxy. In certain embodiments, R 1 is alkoxy or substituted alkoxy. In certain embodiments, R 1 is alkoxy. For example, R 1 may be a C 1 -C6 alkoxy, such as a C 1 -C3 alkoxy. In certain embodiments, R 1 is -OCH 3 . In certain embodiments, R 1 is substituted alkoxy.
  • the alkoxy group may be substituted with one or more groups, such as, but not limited to, alkyl, hydroxy, alkoxy, amino, carboxyl, carboxyl ester, cyano, halogen, acyl, aminoacyl, nitro, alkenyl, alkynyl, and the like.
  • the substituents on the substituted alkoxy may in turn be substituted with one or more groups as described above.
  • the alkoxy is substituted with one or more halogen groups (e.g., F, CI, Br, I).
  • the alkoxy is substituted with one or more iluoro groups.
  • R 1 is -OCHF 2 . In certain embodiments, R 1 is amino or substituted amino. In certain embodiments, R 1 is carboxyl or carboxyl ester. In certain embodiments, R 1 is cyano, halogen, acyl, aminoacyl, or nitro. In certain embodiments, R 1 is alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl.
  • m is an integer from zero to four. In certain embodiments, m is zero. In certain embodiments, m is one. In certain embodiments, m is two. In certain embodiments, m is three. In certain embodiments, m is four.
  • R 2 , R 3 , R 4 , and R 5 are independently selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl.
  • R 2 is hydrogen. In certain embodiments, R 2 is alkyl or substituted alkyl. In certain embodiments, R 2 is hydroxy, alkoxy, or substituted alkoxy. In certain embodiments, R 2 is amino or substituted amino. In certain embodiments, R 2 is carboxyl or carboxyl ester. In certain embodiments, R 2 is cyano, halogen, acyl, aminoacyl, or nitro. In certain embodiments, R 2 is alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl.
  • R 3 is hydrogen. In certain embodiments, R 3 is alkyl or substituted alkyl. In certain embodiments, R 3 is alkyl. For example, R 3 may be a C 1 -C6 alkyl, such as a C 1 -C 3 alkyl. In certain embodiments, R 3 is methyl. In certain embodiments, R 3 is hydroxy, alkoxy, or substituted alkoxy. In certain embodiments, R 3 is amino or substituted amino. In certain embodiments, R 3 is carboxyl or carboxyl ester. In certain embodiments, R 3 is cyano, halogen, acyl, aminoacyl, or nitro. In certain embodiments, R 3 is alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl.
  • R 4 is hydrogen. In certain embodiments, R 4 is alkyl or substituted alkyl. In certain embodiments, R 4 is hydroxy, alkoxy, or substituted alkoxy. In certain embodiments, R 4 is alkoxy. For example, R 4 may be a C 1 -C6 alkoxy, such as a C 1 -C 3 alkoxy. In certain embodiments, R 4 is -OCH 3 . In certain embodiments, R 4 is substituted alkoxy.
  • the alkoxy group may be substituted with one or more groups, such as, but not limited to, alkyl, hydroxy, alkoxy, amino, carboxyl, carboxyl ester, cyano, halogen, acyl, aminoacyl, nitro, alkenyl, alkynyl, and the like.
  • the substituents on the substituted alkoxy may in turn be substituted with one or more groups as described above.
  • the alkoxy is substituted with one or more halogen groups (e.g., F, CI, Br, I).
  • the alkoxy is substituted with one or more fluoro groups.
  • R 4 is -OCH 2 CF 3 .
  • the alkoxy is substituted with an alkoxy group, such as a Ci-C 6 alkoxy, or a Q-C3 alkoxy.
  • R 4 is -0(CH 2 ) 3 OCH 3 .
  • R 4 is amino or substituted amino.
  • R 4 is carboxyl or carboxyl ester.
  • R 4 is cyano, halogen, acyl, aminoacyl, or nitro.
  • R 4 is alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl.
  • R 5 is hydrogen.
  • R 5 is alkyl or substituted alkyl. In certain embodiments, R 5 is alkyl. For example, R 5 may be a Ci-C 6 alkyl, such as a Q-C3 alkyl. In certain embodiments, R 5 is methyl. In certain embodiments, R 5 is hydroxy, alkoxy, or substituted alkoxy. In certain embodiments, R 5 is alkoxy. For example, R 5 may be a Ci-C 6 alkoxy, such as a Q-C3 alkoxy. In certain embodiments, R 5 is -OCH 3 . In certain embodiments, R 5 is amino or substituted amino. In certain embodiments, R 5 is carboxyl or carboxyl ester. In certain embodiments, R 5 is cyano, halogen, acyl, aminoacyl, or nitro. In certain embodiments, R 5 is alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl.
  • omeprazole pantoprazole, lansoprazole, tenatoprazole, esomeraprazole, and rabeprazole is specifically excluded.
  • R 1 is selected from hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocyclyl, and substituted heterocyclyl;
  • R 2 is selected from hydrogen, alkyl, and substituted alkyl
  • R 3 and R 4 are independently selected from hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl;
  • the embodiments include pharmaceutical compositions, which include a compound of Formula lib:
  • R 1 is selected from hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocyclyl, and substituted heterocyclyl;
  • R 2 is selected from hydrogen, alkyl, and substituted alkyl
  • R 3 and R 4 are independently selected from hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl.
  • R 3 is hydrogen. In certain embodiments, R 3 is alkyl or substituted alkyl. In certain embodiments, R 3 is alkyl. For example, R 3 may be a Ci-C 6 alkyl, such as a Ci-C 3 alkyl. In certain embodiments, R 3 is methyl. In certain embodiments, R 3 is hydroxy, alkoxy, or substituted alkoxy. In certain embodiments, R 3 is amino or substituted amino. In certain embodiments, R 3 is carboxyl or carboxyl ester. In certain embodiments, R 3 is cyano, halogen, acyl, aminoacyl, or nitro.
  • R 3 is alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl.
  • R 4 is hydrogen. In certain embodiments, R 4 is alkyl or substituted alkyl. In certain embodiments, R 4 is alkyl. For example, R 4 may be a Ci-C 6 alkyl, such as a C 1 -C 3 alkyl. In certain embodiments, R 4 is methyl. In certain embodiments, R 4 is hydroxy, alkoxy, or substituted alkoxy. In certain embodiments, R 4 is amino or substituted amino. In certain embodiments, R 4 is carboxyl or carboxyl ester. In certain embodiments, R 4 is cyano, halogen, acyl, aminoacyl, or nitro. In certain embodiments, R 4 is alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl.
  • R 1 is selected from hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocyclyl, and substituted heterocyclyl.
  • R 1 is hydrogen. In certain embodiments, R 1 is alkyl or substituted alkyl. In certain embodiments, R 1 is alkyl. For example, R 1 may be a C 1 -C6 alkyl, such as a C 1 -C 3 alkyl. In certain embodiments, R 1 is substituted alkyl.
  • the alkyl group may be substituted with one or more groups, such as, but not limited to, alkyl, hydroxy, alkoxy, amino, carboxyl, carboxyl ester, cyano, halogen, thio, acyl, aminoacyl, nitro, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and the like.
  • the alkyl is substituted with an alkyl group, such as a C 1 -C6 alkyl, or a C 1 -C 3 alkyl.
  • the alkyl is substituted with an alkoxy group, such as a C 1 -C6 alkoxy, or a C 1 -C 3 alkoxy.
  • the alkyl group is substituted with a cycloalkyl group, such as a saturated or unsaturated cycloalkyl group.
  • the alkyl group is substituted with an aryl. Combinations of the above substituents may also be included.
  • the substituents on the substituted alkyl may in turn be substituted with one or more groups as described above, such as, but not limited to, alkyl, hydroxy, alkoxy, amino, carboxyl, carboxyl ester, cyano, halogen (e.g., F, CI, Br, I), thio, acyl, aminoacyl, nitro, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and the like.
  • R 1 is alkoxy or substituted alkoxy.
  • R 1 is cycloalkyl or substituted cycloalkyl.
  • R 1 is cycloalkyl, such as C 3 -Ci 0 cycloalkyl, or a C 3 -C 6 cycloalkyl. In certain embodiments, R 1 is cyclohexyl.
  • R 1 is a substituted cycloalkyl, where the cycloalkyl group is substituted with one or more groups as described above, such as, but not limited to, alkyl, hydroxy, alkoxy, amino, carboxyl, carboxyl ester, cyano, halogen (e.g., F, CI, Br, I), thio, acyl, aminoacyl, nitro, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and the like.
  • groups as described above, such as, but not limited to, alkyl, hydroxy, alkoxy, amino, carboxyl, carboxyl ester, cyano, halogen (e.g., F, CI, Br, I), thio, acyl, aminoacyl, nitro, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and the like.
  • the cycloalkyl group may be substituted with one or more alkyl groups, such as a C 1 -C6 alkyl, or a C 1 -C 3 alkyl (e.g., methyl).
  • R 1 is aryl or substituted aryl.
  • R 1 is heterocyclyl or substituted heterocyclyl.
  • R 1 is selected from the following:
  • R 2 is selected from hydrogen, alkyl, and substituted alkyl. In certain embodiments, R 2 is hydrogen. In certain embodiments, R 2 is selected from alkyl. In certain embodiments, R 2 is substituted alkyl.
  • the embodiments include pharmaceutical compositions formulated for inhalational delivery, de a compound of Formula III:
  • Q 1 is S, O, NH or CH 2 ;
  • Q 2 is N or CH
  • Q 3 is N or CH
  • R 1 is selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl;
  • R 2 is selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl;
  • n is an integer from zero to four;
  • n is an integer from zero to three;
  • Q 1 is S, O, NH or CH 2 .
  • Q 1 is S In certain embodiments, Q 1 is O.
  • Q 1 is NH In certain embodiments, Q 1 is CH 2 .
  • Q 2 is N or CH. In certain embodiments, Q 2 is N. In certain embodiments,
  • Q 3 is N or CH. In certain embodiments, Q 3 is N. In certain embodiments,
  • R 1 is selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl.
  • R 1 is alkyl or substituted alkyl. In certain embodiments, R 1 is hydroxy, alkoxy, or substituted alkoxy. In certain embodiments, R 1 is amino, substituted amino, carboxyl, or carboxyl ester. In certain embodiments, R 1 is cyano, halogen, acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl.
  • R 2 is selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl.
  • R 2 is alkyl or substituted alkyl. In certain embodiments, R 2 is hydroxy, alkoxy, or substituted alkoxy. In certain embodiments, R 2 is amino, substituted amino, carboxyl, or carboxyl ester. In certain embodiments, R 2 is cyano, halogen, acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl.
  • m is an integer from zero to four. In certain embodiments, m is zero. In certain embodiments, m is one. In certain embodiments, m is two. In certain embodiments, m is three. In certain embodiments, m is four.
  • n is an integer from zero to three. In certain embodiments, n is zero. In certain embodiments, n is one. In certain embodiments, n is two. In certain embodiments, n is three.
  • a particular compound of interest, and salts or solvates or stereoisomers thereof for formul the embodiments, is:
  • Particular compounds of interest, and salts or solvates or stereoisomers thereof for formulation according to the embodiments include:
  • the present disclosure provides a pharmaceutical formulation that includes a compound of Formula Xa:
  • R 1 , R 2 and R 3 are independently selected from hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl;
  • R 4 is selected from hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocyclyl, and substituted heterocyclyl; and Q 1 is N or CR 5 , where R 5 , if present, is selected from hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl; and a flowable formulation suitable for delivery by inhalation.
  • the embodiments include pharmaceutical formulations that include a compound of Formula Xb:
  • R 1 , R 2 , R 3 and R 5 are independently selected from hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl; and
  • R 1 , R 2 and R 3 are independently selected from hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl.
  • R 1 is hydrogen. In certain embodiments, R 1 is alkyl or substituted alkyl. In certain embodiments, R 1 is hydroxy, alkoxy, or substituted alkoxy. In certain embodiments, R 1 is amino or substituted amino. In certain embodiments, R 1 is carboxyl or carboxyl ester. In certain embodiments, R 1 is cyano, halogen, acyl, aminoacyl, or nitro. In certain embodiments, R 1 is alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl. In certain embodiments, R 1 is alkyl, such as a Q- Ce alkyl, or a C 1 -C 3 alkyl. In certain embodiments, R 1 is methyl.
  • R 2 is hydrogen. In certain embodiments, R 2 is alkyl or substituted alkyl. In certain embodiments, R 2 is hydroxy, alkoxy, or substituted alkoxy. In certain embodiments, R 2 is amino or substituted amino. In certain embodiments, R 2 is carboxyl or carboxyl ester. In certain embodiments, R 2 is cyano, halogen, acyl, aminoacyl, or nitro. In certain embodiments, R 2 is alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl. In certain embodiments, R 2 is alkyl, such as a d- C alkyl, or a C 1 -C 3 alkyl. In certain embodiments, R 2 is methyl.
  • R 3 is hydrogen. In certain embodiments, R 3 is alkyl or substituted alkyl. In certain embodiments, R 3 is hydroxy, alkoxy, or substituted alkoxy. In certain embodiments, R 3 is amino or substituted amino. In certain embodiments, R 3 is carboxyl or carboxyl ester. In certain embodiments, R 3 is cyano, halogen, acyl, aminoacyl, or nitro. In certain embodiments, R 3 is alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl. In certain embodiments, R 3 is alkyl, such as a Q- C 6 alkyl, or a Q-C3 alkyl. In certain embodiments, R 3 is methyl.
  • R 4 is selected from hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocyclyl, and substituted heterocyclyl.
  • R 4 is hydrogen. In certain embodiments, R 4 is alkyl or substituted alkyl. In certain embodiments, R 4 is alkoxy or substituted alkoxy. In certain embodiments, R 4 is cycloalkyl or substituted cycloalkyl. In certain embodiments, R 4 is aryl or substituted aryl. In certain embodiments, R 4 is heterocyclyl or substituted heterocyclyl.
  • R 5 is selected from hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl.
  • R 5 is hydrogen. In certain embodiments, R 5 is alkyl or substituted alkyl. In certain embodiments, R 5 is hydroxy, alkoxy, or substituted alkoxy. In certain embodiments, R 5 is amino or substituted amino. In certain embodiments, R 5 is carboxyl or carboxyl ester. In certain embodiments, R 5 is cyano, halogen, acyl, aminoacyl, or nitro. In certain embodiments, R 5 is alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl. In certain embodiments, R 5 is alkyl, such as a d- Ce alkyl, or a C 1 -C3 alkyl. In certain embodiments, R 5 is methyl.
  • Particular compounds of interest, and salts or solvates or stereoisomers thereof for formulation according to the embodiments include:
  • DDAH inhibitors as well as compositions, including pharmaceutical compositions (also referred to herein as pharamaceutical formulations), comprising a subject DDAH inhibitor.
  • a DDAH inhibitor has a half-maximal inhibitor concentration of from about 1 nM to about 1 mM, e.g., from about 1 nM to about 10 nM, from about 10 nM to about 15 nM, from about 15 nM to about 25 nM, from about 25 nM to about 50 nM, from about 50 nM to about 75 nM, from about 75 nM to about 100 nM, from about 100 nM to about 150 nM, from about 150 nM to about 200 nM, from about 200 nM to about 250 nM, from about 250 nM to about 300 nM, from about 300 nM to about 350 nM, from about 350 nM to about 400 nM, from about 400 nM to about 450 nM, from about 450 nM to about 500 nM, from about 500 nM to about 750 nM, from about 750 nM to about 1
  • a DDAH inhibitor inhibits enzymatic activity of a DDAH polypeptide by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, or more than 50%, compared to the activity of the DDAH polypeptide in the absence of the inhibitor.
  • a DDAH inhibitor is selective, e.g., the DDAH inhibitor inhibits DDAH enzymatic activity, but does not substantially inhibit enzymes other than DDAH.
  • a subject pharmaceutical formulation comprises a DDAH inhibitor.
  • DDAH inhibitors include a DDAH inhibitor.
  • a formula number is meant to encompass all forms of the formula number.
  • reference to formula (I) is meant to include compounds of formula (la), (lb), and (Ic).
  • the embodiments include pharmaceutical compositions comprising a compound of
  • Q 1 is N or CH
  • R 1 is selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl;
  • R 2 , R 3 , R 4 , and R 5 are independently selected from hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl; and
  • n is an integer from zero to four;
  • the embodiments include pharmaceutical compositions c a compound of Formula lb:
  • R 1 is selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl;
  • R 2 , R 3 , R 4 , and R 5 are independently selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl; and
  • n is an integer from zero to four;
  • the embodiments include pharmaceutical compositions comprising a compound of Formula Ic:
  • R is selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl;
  • R 2 , R 3 , R 4 , and R 5 are independently selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl; and
  • n is an integer from zero to four;
  • Q 1 is N or CH. In certain embodiments, Q 1 is N. In certain embodiments,
  • R 1 is selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl.
  • R 1 is alkyl or substituted alkyl. In certain embodiments, R 1 is hydroxy. In certain embodiments, R 1 is alkoxy or substituted alkoxy. In certain embodiments, R 1 is alkoxy. For example, R 1 may be a C 1 -C6 alkoxy, such as a C 1 -C3 alkoxy. In certain embodiments, R 1 is -OCH 3 . In certain embodiments, R 1 is substituted alkoxy.
  • the alkoxy group may be substituted with one or more groups, such as, but not limited to, alkyl, hydroxy, alkoxy, amino, carboxyl, carboxyl ester, cyano, halogen, acyl, aminoacyl, nitro, alkenyl, alkynyl, and the like.
  • the substituents on the substituted alkoxy may in turn be substituted with one or more groups as described above.
  • the alkoxy is substituted with one or more halogen groups (e.g., F, CI, Br, I).
  • the alkoxy is substituted with one or more iluoro groups.
  • R 1 is -OCHF 2 . In certain embodiments, R 1 is amino or substituted amino. In certain embodiments, R 1 is carboxyl or carboxyl ester. In certain embodiments, R 1 is cyano, halogen, acyl, aminoacyl, or nitro. In certain embodiments, R 1 is alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl.
  • m is an integer from zero to four. In certain embodiments, m is zero. In certain embodiments, m is one. In certain embodiments, m is two. In certain embodiments, m is three. In certain embodiments, m is four.
  • R 2 , R 3 , R 4 , and R 5 are independently selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl.
  • R 2 is hydrogen. In certain embodiments, R 2 is alkyl or substituted alkyl. In certain embodiments, R 2 is hydroxy, alkoxy, or substituted alkoxy. In certain embodiments, R 2 is amino or substituted amino. In certain embodiments, R 2 is carboxyl or carboxyl ester. In certain embodiments, R 2 is cyano, halogen, acyl, aminoacyl, or nitro. In certain embodiments, R 2 is alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl.
  • R 3 is hydrogen. In certain embodiments, R 3 is alkyl or substituted alkyl. In certain embodiments, R 3 is alkyl. For example, R 3 may be a C 1 -C6 alkyl, such as a C 1 -C3 alkyl. In certain embodiments, R 3 is methyl. In certain embodiments, R 3 is hydroxy, alkoxy, or substituted alkoxy. In certain embodiments, R 3 is amino or substituted amino. In certain embodiments, R 3 is carboxyl or carboxyl ester. In certain embodiments, R 3 is cyano, halogen, acyl, aminoacyl, or nitro. In certain embodiments, R 3 is alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl.
  • R 4 is hydrogen. In certain embodiments, R 4 is alkyl or substituted alkyl. In certain embodiments, R 4 is hydroxy, alkoxy, or substituted alkoxy. In certain embodiments, R 4 is alkoxy. For example, R 4 may be a Ci-C 6 alkoxy, such as a Q-C 3 alkoxy. In certain embodiments, R 4 is -OCH 3 . In certain embodiments, R 4 is substituted alkoxy.
  • the alkoxy group may be substituted with one or more groups, such as, but not limited to, alkyl, hydroxy, alkoxy, amino, carboxyl, carboxyl ester, cyano, halogen, acyl, aminoacyl, nitro, alkenyl, alkynyl, and the like.
  • the substituents on the substituted alkoxy may in turn be substituted with one or more groups as described above.
  • the alkoxy is substituted with one or more halogen groups (e.g., F, CI, Br, I).
  • the alkoxy is substituted with one or more fluoro groups.
  • R 4 is -OCH 2 CF 3 .
  • the alkoxy is substituted with an alkoxy group, such as a Ci-C 6 alkoxy, or a Q-C 3 alkoxy.
  • R 4 is -0(CH 2 ) 3 0CH 3 .
  • R 4 is amino or substituted amino.
  • R 4 is carboxyl or carboxyl ester.
  • R 4 is cyano, halogen, acyl, aminoacyl, or nitro.
  • R 4 is alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl. [00256]
  • R 5 is hydrogen.
  • R 5 is alkyl or substituted alkyl. In certain embodiments, R 5 is alkyl. For example, R 5 may be a Ci-C 6 alkyl, such as a Q-C3 alkyl. In certain embodiments, R 5 is methyl. In certain embodiments, R 5 is hydroxy, alkoxy, or substituted alkoxy. In certain embodiments, R 5 is alkoxy. For example, R 5 may be a Ci-C 6 alkoxy, such as a Q-C3 alkoxy. In certain embodiments, R 5 is -OCH 3 . In certain embodiments, R 5 is amino or substituted amino. In certain embodiments, R 5 is carboxyl or carboxyl ester. In certain embodiments, R 5 is cyano, halogen, acyl, aminoacyl, or nitro. In certain embodiments, R 5 is alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl.
  • omeprazole pantoprazole, lansoprazole, tenatoprazole, esomeraprazole, and rabeprazole is specifically excluded.
  • R 1 is selected from hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocyclyl, and substituted heterocyclyl;
  • R 2 is selected from hydrogen, alkyl, and substituted alkyl
  • R 3 and R 4 are independently selected from hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl;
  • the embodiments include pharmaceutical compositions, which include a compound of Formula lib:
  • R 1 is selected from hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocyclyl, and substituted heterocyclyl;
  • R 2 is selected from hydrogen, alkyl, and substituted alkyl
  • R 3 and R 4 are independently selected from hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl.
  • R 3 is hydrogen. In certain embodiments, R 3 is alkyl or substituted alkyl. In certain embodiments, R 3 is alkyl. For example, R 3 may be a Ci-C 6 alkyl, such as a Ci-C 3 alkyl. In certain embodiments, R 3 is methyl. In certain embodiments, R 3 is hydroxy, alkoxy, or substituted alkoxy. In certain embodiments, R 3 is amino or substituted amino. In certain embodiments, R 3 is carboxyl or carboxyl ester. In certain embodiments, R 3 is cyano, halogen, acyl, aminoacyl, or nitro. In certain embodiments, R 3 is alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl.
  • R 4 is hydrogen. In certain embodiments, R 4 is alkyl or substituted alkyl. In certain embodiments, R 4 is alkyl. For example, R 4 may be a Ci-C 6 alkyl, such as a Ci-C 3 alkyl. In certain embodiments, R 4 is methyl. In certain embodiments, R 4 is hydroxy, alkoxy, or substituted alkoxy. In certain embodiments, R 4 is amino or substituted amino. In certain embodiments, R 4 is carboxyl or carboxyl ester. In certain embodiments, R 4 is cyano, halogen, acyl, aminoacyl, or nitro. In certain embodiments, R 4 is alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl.
  • R 1 is selected from hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocyclyl, and substituted heterocyclyl.
  • R 1 is hydrogen. In certain embodiments, R 1 is alkyl or substituted alkyl. In certain embodiments, R 1 is alkyl. For example, R 1 may be a C 1 -C6 alkyl, such as a C 1 -C 3 alkyl. In certain embodiments, R 1 is substituted alkyl.
  • the alkyl group may be substituted with one or more groups, such as, but not limited to, alkyl, hydroxy, alkoxy, amino, carboxyl, carboxyl ester, cyano, halogen, thio, acyl, aminoacyl, nitro, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and the like.
  • the alkyl is substituted with an alkyl group, such as a C 1 -C6 alkyl, or a C 1 -C 3 alkyl.
  • the alkyl is substituted with an alkoxy group, such as a C 1 -C6 alkoxy, or a C 1 -C 3 alkoxy.
  • the alkyl group is substituted with a cycloalkyl group, such as a saturated or unsaturated cycloalkyl group.
  • the alkyl group is substituted with an aryl. Combinations of the above substituents may also be included.
  • the substituents on the substituted alkyl may in turn be substituted with one or more groups as described above, such as, but not limited to, alkyl, hydroxy, alkoxy, amino, carboxyl, carboxyl ester, cyano, halogen (e.g., F, CI, Br, I), thio, acyl, aminoacyl, nitro, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and the like.
  • R 1 is alkoxy or substituted alkoxy.
  • R 1 is cycloalkyl or substituted cycloalkyl.
  • R 1 is cycloalkyl, such as C 3 -Ci 0 cycloalkyl, or a C 3 -C 6 cycloalkyl. In certain embodiments, R 1 is cyclohexyl.
  • R 1 is a substituted cycloalkyl, where the cycloalkyl group is substituted with one or more groups as described above, such as, but not limited to, alkyl, hydroxy, alkoxy, amino, carboxyl, carboxyl ester, cyano, halogen (e.g., F, CI, Br, I), thio, acyl, aminoacyl, nitro, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and the like.
  • groups as described above, such as, but not limited to, alkyl, hydroxy, alkoxy, amino, carboxyl, carboxyl ester, cyano, halogen (e.g., F, CI, Br, I), thio, acyl, aminoacyl, nitro, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and the like.
  • the cycloalkyl group may be substituted with one or more alkyl groups, such as a C 1 -C6 alkyl, or a C 1 -C 3 alkyl (e.g., methyl).
  • R 1 is aryl or substituted aryl.
  • R 1 is heterocyclyl or substituted heterocyclyl.
  • R 1 is selected from the following:
  • R 2 is selected from hydrogen, alkyl, and substituted alkyl. In certain embodiments, R 2 is hydrogen. In certain embodiments, R 2 is selected from alkyl. In certain embodiments, R 2 is substituted alkyl.
  • the embodiments include pharmaceutical compositions comprising a compound of Formula
  • Q 1 is S, O, NH or CH 2 ;
  • Q 2 is N or CH
  • Q 3 is N or CH
  • R 1 is selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl;
  • R 2 is selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl;
  • n is an integer from zero to four;
  • n is an integer from zero to three;
  • Q 1 is S, O, NH or CH 2 .
  • Q 1 is S In certain embodiments, Q 1 is O.
  • Q 1 is NH In certain embodiments, Q 1 is CH 2 .
  • Q 2 is N or CH. In certain embodiments, Q 2 is N. In certain embodiments, Q 2 is CH.
  • Q 3 is N or CH. In certain embodiments, Q 3 is N. In certain embodiments, Q 3 is CH.
  • R 1 is selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl.
  • R 1 is alkyl or substituted alkyl. In certain embodiments, R 1 is hydroxy, alkoxy, or substituted alkoxy. In certain embodiments, R 1 is amino, substituted amino, carboxyl, or carboxyl ester. In certain embodiments, R 1 is cyano, halogen, acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl.
  • R 2 is selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl.
  • R 2 is alkyl or substituted alkyl. In certain embodiments, R 2 is hydroxy, alkoxy, or substituted alkoxy. In certain embodiments, R 2 is amino, substituted amino, carboxyl, or carboxyl ester. In certain embodiments, R 2 is cyano, halogen, acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl.
  • m is an integer from zero to four. In certain embodiments, m is zero. In certain embodiments, m is one. In certain embodiments, m is two. In certain embodiments, m is three. In certain embodiments, m is four.
  • n is an integer from zero to three. In certain embodiments, n is zero. In certain embodiments, n is one. In certain embodiments, n is two. In certain embodiments, n is three.
  • a particular compound of interest, and salts or solvates or stereoisomers thereof for formul the embodiments, is:
  • Particular compounds of interest, and salts or solvates or stereoisomers thereof for formulation according to the embodiments include:
  • the present disclosure provides a pharmaceutical formulation that includes a compound of Formula Xa:
  • R 1 , R 2 and R 3 are independently selected from hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl;
  • R 4 is selected from hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocyclyl, and substituted heterocyclyl; and Q 1 is N or CR 5 , where R 5 , if present, is selected from hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl; and a pharmaceutically acceptable excipient.
  • the embodiments include pharmaceutical formulations that include a compound of Formula Xb:
  • R 1 , R 2 , R 3 and R 5 are independently selected from hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl; and
  • R 1 , R 2 and R 3 are independently selected from hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl.
  • R 1 is hydrogen. In certain embodiments, R 1 is alkyl or substituted alkyl. In certain embodiments, R 1 is hydroxy, alkoxy, or substituted alkoxy. In certain embodiments, R 1 is amino or substituted amino. In certain embodiments, R 1 is carboxyl or carboxyl ester. In certain embodiments, R 1 is cyano, halogen, acyl, aminoacyl, or nitro. In certain embodiments, R 1 is alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl. In certain embodiments, R 1 is alkyl, such as a Q- Ce alkyl, or a C 1 -C 3 alkyl. In certain embodiments, R 1 is methyl.
  • R 2 is hydrogen. In certain embodiments, R 2 is alkyl or substituted alkyl. In certain embodiments, R 2 is hydroxy, alkoxy, or substituted alkoxy. In certain embodiments, R 2 is amino or substituted amino. In certain embodiments, R 2 is carboxyl or carboxyl ester. In certain embodiments, R 2 is cyano, halogen, acyl, aminoacyl, or nitro. In certain embodiments, R 2 is alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl. In certain embodiments, R 2 is alkyl, such as a d- C alkyl, or a C 1 -C 3 alkyl. In certain embodiments, R 2 is methyl.
  • R 3 is hydrogen. In certain embodiments, R 3 is alkyl or substituted alkyl. In certain embodiments, R 3 is hydroxy, alkoxy, or substituted alkoxy. In certain embodiments, R 3 is amino or substituted amino. In certain embodiments, R 3 is carboxyl or carboxyl ester. In certain embodiments, R 3 is cyano, halogen, acyl, aminoacyl, or nitro. In certain embodiments, R 3 is alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl. In certain embodiments, R 3 is alkyl, such as a Q- C 6 alkyl, or a Q-C 3 alkyl. In certain embodiments, R 3 is methyl.
  • R 4 is selected from hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocyclyl, and substituted heterocyclyl.
  • R 4 is hydrogen. In certain embodiments, R 4 is alkyl or substituted alkyl. In certain embodiments, R 4 is alkoxy or substituted alkoxy. In certain embodiments, R 4 is cycloalkyl or substituted cycloalkyl. In certain embodiments, R 4 is aryl or substituted aryl. In certain embodiments, R 4 is heterocyclyl or substituted heterocyclyl.
  • R 5 is selected from hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl.
  • R 5 is hydrogen. In certain embodiments, R 5 is alkyl or substituted alkyl. In certain embodiments, R 5 is hydroxy, alkoxy, or substituted alkoxy. In certain embodiments, R 5 is amino or substituted amino. In certain embodiments, R 5 is carboxyl or carboxyl ester. In certain embodiments, R 5 is cyano, halogen, acyl, aminoacyl, or nitro. In certain embodiments, R 5 is alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl. In certain embodiments, R 5 is alkyl, such as a d- Ce alkyl, or a C 1 -C 3 alkyl. In certain embodiments, R 5 is methyl.
  • Particular compounds of interest, and salts or solvates or stereoisomers thereof for formulation according to the embodiments include:
  • the present disclosure provides pharmaceutical compositions comprising a compound of any one of Formulas I-X.
  • the present disclosure provides pharmaceutical compositions comprising a compound of Formula I; e.g., the present disclosure provides pharmaceutical compositions comprising a compound of any one of Formula la, Formula lb, and Formula Ic.
  • the present disclosure provides pharmaceutical compositions comprising a compound of Formula II, comprising a compound of Formula III, comprising a compound of one of Formulas IV-IX, or a compound of Formula X.
  • a compound of any one of Formulas I-X is prepared in a pharmaceutically acceptable composition(s) for delivery to a host.
  • a composition comprising an active agent can comprise a pharmaceutically acceptable excipient, a variety of which are known in the art and need not be discussed in detail herein.
  • Pharmaceutically acceptable excipients have been amply described in a variety of publications, including, for example, A. Gennaro (1995) "Remington: The Science and Practice of Pharmacy", 19th edition, Lippincott, Williams, & Wilkins.
  • the active agent(s) may be administered to the host using any convenient means capable of resulting in the desired therapeutic effect or clinical outcome.
  • an active agent can be incorporated into a variety of formulations for therapeutic administration. More particularly, an active agent can be formulated into pharmaceutical compositions by combination with appropriate, pharmaceutically acceptable carriers or diluents, and may be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants and aerosols.
  • an active agent may be administered in the form of its pharmaceutically acceptable salt, or an active agent may also be used alone or in appropriate association, as well as in combination, with other pharmaceutically active compounds.
  • the following methods and excipients are merely exemplary and are in no way limiting.
  • an active agent can be used alone or in combination with appropriate additives to make tablets, powders, granules or capsules, for example, with conventional additives, such as lactose, mannitol, corn starch or potato starch; with binders, such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatins; with disintegrators, such as corn starch, potato starch or sodium carboxymethylcellulose; with lubricants, such as talc or magnesium stearate; and if desired, with diluents, buffering agents, moistening agents, preservatives and flavoring agents.
  • conventional additives such as lactose, mannitol, corn starch or potato starch
  • binders such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatins
  • disintegrators such as corn starch, potato starch or sodium carboxymethylcellulose
  • lubricants such as talc or magnesium stearate
  • An active agent can be formulated into preparations for injection by dissolving, suspending or emulsifying them in an aqueous or nonaqueous solvent, such as vegetable or other similar oils, synthetic aliphatic acid glycerides, esters of higher aliphatic acids or propylene glycol; and if desired, with conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers and preservatives.
  • an aqueous or nonaqueous solvent such as vegetable or other similar oils, synthetic aliphatic acid glycerides, esters of higher aliphatic acids or propylene glycol.
  • An active agent can be utilized in aerosol formulation to be administered via inhalation.
  • the compounds of the present invention can be formulated into pressurized acceptable propellants such as dichlorodifluoromethane, propane, nitrogen and the like.
  • an active agent can be made into suppositories by mixing with a variety of bases such as emulsifying bases or water-soluble bases.
  • An active agent can be administered rectally via a suppository.
  • the suppository can include vehicles such as cocoa butter, carbowaxes and polyethylene glycols, which melt at body temperature, yet are solidified at room temperature.
  • Unit dosage forms for oral or rectal administration such as syrups, elixirs, and suspensions may be provided wherein each dosage unit, for example, teaspoonful, tablespoonful, tablet or suppository, contains a predetermined amount of the composition containing one or more inhibitors.
  • unit dosage forms for injection or intravenous administration may comprise an active agent in a composition as a solution in sterile water, normal saline or another pharmaceutically acceptable carrier.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human and animal subjects, each unit containing a predetermined quantity of an active agent calculated in an amount sufficient to produce the desired effect in association with a pharmaceutically acceptable diluent, carrier or vehicle.
  • the specifications for a suitable dosage form depend, e.g., on the particular active agent employed and the effect to be achieved, and the
  • an active agent can be formulated in suppositories and, in some cases, aerosol and intranasal compositions.
  • the vehicle composition can include traditional binders and carriers such as, polyalkylene glycols, or triglycerides.
  • Such suppositories may be formed from mixtures containing the active ingredient in the range of about 0.5% to about 10% (w/w), e.g., about 1% to about 2%.
  • Intranasal formulations will usually include vehicles that neither cause irritation to the nasal mucosa nor significantly disturb ciliary function. Diluents such as water, aqueous saline or other known substances can be employed with the subject invention.
  • the nasal formulations may also contain preservatives such as, but not limited to, chlorobutanol and benzalkonium chloride.
  • a surfactant may be present to enhance absorption of an active agent by the nasal mucosa.
  • An active agent can be administered in a composition suitable for injection.
  • injectable compositions are prepared as liquid solutions or suspensions; solid forms suitable for solution in, or suspension in, liquid vehicles prior to injection may also be prepared.
  • the preparation may also be emulsified or the active ingredient encapsulated in liposome vehicles.
  • Suitable excipient vehicles are, for example, water, saline, dextrose, glycerol, ethanol, or the like, and combinations thereof.
  • the vehicle may contain minor amounts of auxiliary substances such as wetting or emulsifying agents or pH buffering agents.
  • auxiliary substances such as wetting or emulsifying agents or pH buffering agents.
  • Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in the art. See, e.g., Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania, 17th edition, 1985.
  • the composition or formulation to be administered will, in any event, contain a quantity of the agent adequate to achieve the desired state in the subject being treated.
  • the pharmaceutically acceptable excipients such as vehicles, adjuvants, carriers or diluents, are readily available to the public.
  • pharmaceutically acceptable auxiliary substances such as pH adjusting and buffering agents, tonicity adjusting agents, stabilizers, wetting agents and the like, are readily available to the public.
  • An active agent is administered in an amount that provides for inhibition of DDAH in a tissue, e.g., an active agent is administered in an amount that provides for inhibition of DDAH in a tissue over a period of time of from about 1 hour to at least about 48 hours, or more than 48 hours.
  • an active agent is administered in an amount that provides for at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, or more than 50%, inhibition of DDAH enzymatic activity in a tissue, e.g., an active agent is administered in an amount that provides for inhibition of DDAH in a tissue over a period of time of from about 1 hour to at least about 48 hours, or more than 48 hours.
  • a compound of any one of Formulas I-X is present in a unit dosage form in an amount of from about 10 mg to about 50 mg, e.g., from about 10 mg to about 15 mg, from about 15 mg to about 20 mg, from about 20 mg to about 25 mg, from about 25 mg to about 30 mg, from about 30 mg to about 35 mg, from about 35 mg to about 40 mg, from about 40 mg to about 45 mg, or from about 45 mg to about 50 mg.
  • a compound of any one of Formulas I-X is present in a unit dosage form in an amount of from about 50 mg to about 500 mg.
  • a compound of any one of Formulas I-X is present in a unit dosage form in an amount of from about 50 mg to about 60 mg, from about 60 mg to about 70 mg, from about 70 mg to about 80 mg, from about 80 mg to about 90 mg, from about 90 mg to about 100 mg, from about 90 mg to about 100 mg from about 100 mg to about 150 mg, from about 150 mg to about 175 mg, from about 175 mg to about 200 mg, from about 200 mg to about 250 mg, from about 250 mg to about 300 mg, from about 300 mg to about 350 mg, from about 350 mg to about 400 mg, from about 400 mg to about 450 mg, or from about 450 mg to about 500 mg.
  • a compound of any one of Formulas I-X is present in an oral unit dosage form in an amount of from about 50 mg to about 500 mg.
  • a compound of any one of Formulas I-X is present in an oral unit dosage form in an amount of from about 50 mg to about 60 mg, from about 60 mg to about 70 mg, from about 70 mg to about 80 mg, from about 80 mg to about 90 mg, from about 90 mg to about 100 mg from about 100 mg to about 150 mg, from about 150 mg to about 175 mg, from about 175 mg to about 200 mg, from about 200 mg to about 250 mg, from about 250 mg to about 300 mg, from about 300 mg to about 350 mg, from about 350 mg to about 400 mg, from about 400 mg to about 450 mg, or from about 450 mg to about 500 mg.
  • a compound of any one of Formulas I-X is present in an intravenous unit dosage form in an amount of from about 50 mg to about 500 mg.
  • a compound of any one of Formulas I-X is present in an oral unit dosage form in an amount of from about 50 mg to about 60 mg, from about 60 mg to about 70 mg, from about 70 mg to about 80 mg, from about 80 mg to about 90 mg, from about 90 mg to about 100 mg from about 100 mg to about 150 mg, from about 150 mg to about 175 mg, from about 175 mg to about 200 mg, from about 200 mg to about 250 mg, from about 250 mg to about 300 mg, from about 300 mg to about 350 mg, from about 350 mg to about 400 mg, from about 400 mg to about 450 mg, or from about 450 mg to about 500 mg.
  • a "unit dosage form” can be a liquid dosage form (e.g., a teaspoon, a tablespoon, 1 ml, 5 ml, 10 ml, etc.); a semi-solid dosage form (e.g., a gel capsule); a solid dosage form (e.g., a tablet, a powder, etc.).
  • a liquid dosage form e.g., a teaspoon, a tablespoon, 1 ml, 5 ml, 10 ml, etc.
  • a semi-solid dosage form e.g., a gel capsule
  • a solid dosage form e.g., a tablet, a powder, etc.
  • an active agent e.g., a compound of any one of Formulas I-X
  • an active agent is administered in an amount in the range of from about 10 mg per day to about 20 mg/day, from about 20 mg/day to about 30 mg/day, from about 30 mg/day to about 40 mg/day, from about 40 mg/day to about 50 mg/day, from about 50 mg/day to about 60 mg/day, from about 60 mg/day to about 70 mg/day, from about 70 mg/day to about 80 mg/day, from about 80 mg/day to about 90 mg/day, or from about 90 mg/day to about 100 mg/day.
  • an active agent of Formula la, lb, or Ic is administered to treat IPF, in an individual having IPF, in an amount in the range of from about 10 mg per day to about 20 mg/day, from about 20 mg/day to about 30 mg/day, from about 30 mg/day to about 40 mg/day, from about 40 mg/day to about 50 mg/day, from about 50 mg/day to about 60 mg/day, from about 60 mg/day to about 70 mg/day, from about 70 mg/day to about 80 mg/day, from about 80 mg/day to about 90 mg/day, or from about 90 mg/day to about 100 mg/day.
  • an active agent of Formula la, lb, or Ic is administered via oral administration to treat IPF, in an individual having IPF, in an amount in the range of from about 10 mg per day to about 20 mg/day, from about 20 mg/day to about 30 mg/day, from about 30 mg/day to about 40 mg/day, from about 40 mg/day to about 50 mg/day, from about 50 mg/day to about 60 mg/day, from about 60 mg/day to about 70 mg/day, from about 70 mg/day to about 80 mg/day, from about 80 mg/day to about 90 mg/day, or from about 90 mg/day to about 100 mg/day.
  • an active agent of Formula la, lb, or Ic is administered via oral administration to treat IPF, in an individual having IPF, in an amount in the range of from about 10 mg per day to about 20 mg/day, from about 20 mg/day to about 30 mg/day, from about 30 mg/day to about 40 mg/day, from about 40 mg/day to about 50 mg/day, from about 50 mg/day
  • an active agent of Formula la, lb, or Ic is administered via inhalational administration to treat IPF, in an individual having IPF, in an amount in the range of from about 10 mg per day to about 20 mg/day, from about 20 mg/day to about 30 mg/day, from about 30 mg/day to about 40 mg/day, from about 40 mg/day to about 50 mg/day, from about 50 mg/day to about 60 mg/day, from about 60 mg/day to about 70 mg/day, from about 70 mg/day to about 80 mg/day, from about 80 mg/day to about 90 mg/day, or from about 90 mg/day to about 100 mg/day.
  • an active agent of Formula la, lb, or Ic is administered via intravenous administration to treat IPF, in an individual having IPF, in an amount in the range of from about 10 mg per day to about 20 mg/day, from about 20 mg/day to about 30 mg/day, from about 30 mg/day to about 40 mg/day, from about 40 mg/day to about 50 mg/day, from about 50 mg/day to about 60 mg/day, from about 60 mg/day to about 70 mg/day, from about 70 mg/day to about 80 mg/day, from about 80 mg/day to about 90 mg/day, or from about 90 mg/day to about 100 mg/day.
  • an active agent is administered in an amount greater than 100 mg per day, e.g., where the total daily dosage is greater than 100 mg.
  • an active agent can be administered in an amount of from about 100 mg/day to about 150 mg/day, from about 150 mg/day to about 200 mg/day, from about 200 mg/day to about 250 mg/day, from about 250 mg/day to about 300 mg/day, from about 300 mg/day to about 350 mg/day, from about 400 mg/day to about 425 mg/day, from about 425 mg/day to about 450 mg/day, from about 450 mg/day to about 500 mg/day, from about 500 mg/day to about 550 mg/day, from about 550 mg/day to about 600 mg/day, from about 600 mg/day to about 650 mg/day, from about 650 mg/day to about 700 mg/day, from about 700 mg/day to about 750 mg/day, from about 750 mg/day to about 800 mg/day, from about 800 mg/day to about
  • an active agent can be administered in an amount of from about 100 mg/day to about 250 mg/day, from about 250 mg/day to about 500 mg/day, from about 500 mg/day to about 1000 mg/day, from about 1000 mg/day to about 1500 mg/day, from about 1500 mg/day to about 2000 mg/day, or from about 2000 mg/day to about 2500 mg/day.
  • a compound of Formula I (e.g., a compound of any one of Formulas la, lb, and Ic) can be administered in an amount of from about 100 mg/day to about 150 mg/day, from about 150 mg/day to about 200 mg/day, from about 200 mg/day to about 250 mg/day, from about 250 mg/day to about 300 mg/day, from about 300 mg/day to about 350 mg/day, from about 400 mg/day to about 425 mg/day, from about 425 mg/day to about 450 mg/day, from about 450 mg/day to about 500 mg/day, from about 500 mg/day to about 550 mg/day, from about 550 mg/day to about 600 mg/day, from about 600 mg/day to about 650 mg/day, from about 650 mg/day to about 700 mg/day, from about 700 mg/day to about 750 mg/day, from about 750 mg/day to about 800 mg/day, from about 800 mg/day to about 900 mg/day, from about 100 mg/day to about 150 mg
  • a compound of Formula I (e.g., a compound of any one of Formulas la, lb, and Ic) can be administered in an amount of from about 100 mg/day to about 250 mg/day, from about 250 mg/day to about 500 mg/day, from about 500 mg/day to about 1000 mg/day, from about 1000 mg/day to about 1500 mg/day, from about 1500 mg/day to about 2000 mg/day, or from about 2000 mg/day to about 2500 mg/day.
  • an active agent is administered via oral administration in an amount greater than 100 mg per day, e.g., where the total daily dosage is greater than 100 mg.
  • an active agent can be administered via oral administration in an amount of from about 100 mg/day to about 150 mg/day, from about 150 mg/day to about 200 mg/day, from about 200 mg/day to about 250 mg/day, from about 250 mg/day to about 300 mg/day, from about 300 mg/day to about 350 mg/day, from about 400 mg/day to about 425 mg/day, from about 425 mg/day to about 450 mg/day, from about 450 mg/day to about 500 mg/day, from about 500 mg/day to about 550 mg/day, from about 550 mg/day to about 600 mg/day, from about 600 mg/day to about 650 mg/day, from about 650 mg/day to about 700 mg/day, from about 700 mg/day to about 750 mg/day, from about 750 mg/day to about 800 mg/day, from about 800
  • an active agent can be administered via oral administration in an amount of from about 100 mg/day to about 250 mg/day, from about 250 mg/day to about 500 mg/day, from about 500 mg/day to about 1000 mg/day, from about 1000 mg/day to about 1500 mg/day, from about 1500 mg/day to about 2000 mg/day, or from about 2000 mg/day to about 2500 mg/day.
  • a compound of Formula I (e.g., a compound of any one of Formulas la, lb, and Ic) can be administered via oral administration in an amount of from about 100 mg/day to about 150 mg/day, from about 150 mg/day to about 200 mg/day, from about 200 mg/day to about 250 mg/day, from about 250 mg/day to about 300 mg/day, from about 300 mg/day to about 350 mg/day, from about 400 mg/day to about 425 mg/day, from about 425 mg/day to about 450 mg/day, from about 450 mg/day to about 500 mg/day, from about 500 mg/day to about 550 mg/day, from about 550 mg/day to about 600 mg/day, from about 600 mg/day to about 650 mg/day, from about 650 mg/day to about 700 mg/day, from about 700 mg/day to about 750 mg/day, from about 750 mg/day to about 800 mg/day, from about 800 mg/day to about 900 mg/day
  • a compound of Formula I (e.g., a compound of any one of Formulas la, lb, and Ic) can be administered via oral administration in an amount of from about 100 mg/day to about 250 mg/day, from about 250 mg/day to about 500 mg/day, from about 500 mg/day to about 1000 mg/day, from about 1000 mg/day to about 1500 mg/day, from about 1500 mg/day to about 2000 mg/day, or from about 2000 mg/day to about 2500 mg/day.
  • a compound of Formula I e.g., a compound of any one of Formulas la, lb, and Ic
  • an active agent is administered via an inhalational route of administration in an amount greater than 100 mg per day, e.g., where the total daily dosage is greater than 100 mg.
  • an active agent can be administered via an inhalational route of
  • administering in an amount of from about 100 mg/day to about 150 mg/day, from about 150 mg/day to about 200 mg/day, from about 200 mg/day to about 250 mg/day, from about 250 mg/day to about 300 mg/day, from about 300 mg/day to about 350 mg/day, from about 400 mg/day to about 425 mg/day, from about 425 mg/day to about 450 mg/day, from about 450 mg/day to about 500 mg/day, from about 500 mg/day to about 550 mg/day, from about 550 mg/day to about 600 mg/day, from about 600 mg/day to about 650 mg/day, from about 650 mg/day to about 700 mg/day, from about 700 mg/day to about 750 mg/day, from about 750 mg/day to about 800 mg/day, from about 800 mg/day to about 900 mg/day, from about 900 mg/day to about 1000 mg/day, from about 1000 mg/day to about 1500 mg/day, from about 1500 mg/day to about 2000 mg/day, or from
  • an active agent can be administered via an inhalational route of administration in an amount of from about 100 mg/day to about 250 mg/day, from about 250 mg/day to about 500 mg/day, from about 500 mg/day to about 1000 mg/day, from about 1000 mg/day to about 1500 mg/day, from about 1500 mg/day to about 2000 mg/day, or from about 2000 mg/day to about 2500 mg/day.
  • a compound of Formula I (e.g., a compound of any one of Formulas la, lb, and Ic) can be administered via an inhalational route of administration in an amount of from about 100 mg/day to about 150 mg/day, from about 150 mg/day to about 200 mg/day, from about 200 mg/day to about 250 mg/day, from about 250 mg/day to about 300 mg/day, from about 300 mg/day to about 350 mg/day, from about 400 mg/day to about 425 mg/day, from about 425 mg/day to about 450 mg/day, from about 450 mg/day to about 500 mg/day, from about 500 mg/day to about 550 mg/day, from about 550 mg/day to about 600 mg/day, from about 600 mg/day to about 650 mg/day, from about 650 mg/day to about 700 mg/day, from about 700 mg/day to about 750 mg/day, from about 750 mg/day to about 800 mg/day, from about 800 mg/day to
  • a compound of Formula I (e.g., a compound of any one of Formulas la, lb, and Ic) can be administered via an inhalational route of administration in an amount of from about 100 mg/day to about 250 mg/day, from about 250 mg/day to about 500 mg/day, from about 500 mg/day to about 1000 mg/day, from about 1000 mg/day to about 1500 mg/day, from about 1500 mg/day to about 2000 mg/day, or from about 2000 mg/day to about 2500 mg/day.
  • an inhalational route of administration in an amount of from about 100 mg/day to about 250 mg/day, from about 250 mg/day to about 500 mg/day, from about 500 mg/day to about 1000 mg/day, from about 1000 mg/day to about 1500 mg/day, from about 1500 mg/day to about 2000 mg/day, or from about 2000 mg/day to about 2500 mg/day.
  • an active agent is administered via intravenous administration in an amount greater than 100 mg per day, e.g., where the total daily dosage is greater than 100 mg.
  • an active agent can be administered via intravenous administration in an amount of from about 100 mg/day to about 150 mg/day, from about 150 mg/day to about 200 mg/day, from about 200 mg/day to about 250 mg/day, from about 250 mg/day to about 300 mg/day, from about 300 mg/day to about 350 mg/day, from about 400 mg/day to about 425 mg/day, from about 425 mg/day to about 450 mg/day, from about 450 mg/day to about 500 mg/day, from about 500 mg/day to about 550 mg/day, from about 550 mg/day to about 600 mg/day, from about 600 mg/day to about 650 mg/day, from about 650 mg/day to about 700 mg/day, from about 700 mg/day to about 750 mg/day, from about 750 mg/day to about 800 mg/day
  • an active agent can be administered via intravenous administration in an amount of from about 100 mg/day to about 250 mg/day, from about 250 mg/day to about 500 mg/day, from about 500 mg/day to about 1000 mg/day, from about 1000 mg/day to about 1500 mg/day, from about 1500 mg/day to about 2000 mg/day, or from about 2000 mg/day to about 2500 mg/day.
  • a compound of Formula I (e.g., a compound of any one of Formulas la, lb, and Ic) can be administered via intravenous administration in an amount of from about 100 mg/day to about 150 mg/day, from about 150 mg/day to about 200 mg/day, from about 200 mg/day to about 250 mg/day, from about 250 mg/day to about 300 mg/day, from about 300 mg/day to about 350 mg/day, from about 400 mg/day to about 425 mg/day, from about 425 mg/day to about 450 mg/day, from about 450 mg/day to about 500 mg/day, from about 500 mg/day to about 550 mg/day, from about 550 mg/day to about 600 mg/day, from about 600 mg/day to about 650 mg/day, from about 650 mg/day to about 700 mg/day, from about 700 mg/day to about 750 mg/day, from about 750 mg/day to about 800 mg/day, from about 800 mg/day to about 900 mg
  • a compound of Formula I (e.g., a compound of any one of Formulas la, lb, and Ic) can be administered via intravenous administration in an amount of from about 100 mg/day to about 250 mg/day, from about 250 mg/day to about 500 mg/day, from about 500 mg/day to about 1000 mg/day, from about 1000 mg/day to about 1500 mg/day, from about 1500 mg/day to about 2000 mg/day, or from about 2000 mg/day to about 2500 mg/day.
  • a compound of Formula I e.g., a compound of any one of Formulas la, lb, and Ic
  • intravenous administration in an amount of from about 100 mg/day to about 250 mg/day, from about 250 mg/day to about 500 mg/day, from about 500 mg/day to about 1000 mg/day, from about 1000 mg/day to about 1500 mg/day, from about 1500 mg/day to about 2000 mg/day, or from about 2000 mg/day to about 2500 mg/day.
  • a single dose of an active agent is administered.
  • multiple doses of an active agent are administered.
  • an active agent is administered twice daily (qid), daily (qd), every other day (qod), every third day, three times per week (tiw), or twice per week (biw) over a period of time.
  • an active agent is administered qid, qd, qod, tiw, or biw over a period of from one day to about 2 years or more.
  • an active agent is administered at any of the aforementioned frequencies for one week, two weeks, one month, two months, six months, one year, or two years, or more, depending on various factors.
  • a first active agent and a second active agent can be administered in separate formulations.
  • a first active agent and a second active agent can be administered substantially simultaneously, or within about 30 minutes, about 1 hour, about 2 hours, about 4 hours, about 8 hours, about 16 hours, about 24 hours, about 36 hours, about 72 hours, about 4 days, about 7 days, or about 2 weeks of one another.
  • a target dosage of an active agent can be considered to be a dosage that provides for a sustained tissue concentration of the active agent of greater than 3 ⁇ .
  • a target dosage of an active agent can be considered to be a dosage that provides for a sustained tissue concentration of the active agent of from about 3 ⁇ to about 100 ⁇ , or greater than 100 ⁇ , within a time period of from about 30 minutes to 120 hours (e.g., within a time period of from about 30 minutes to about 6 hours, from about 6 hours to about 12 hours, from about 12 hours to about 24 hours, from about 24 hours to about 48 hours, from about 48 hours to about 72 hours, from about 72 hours to about 96 hours, or from about 120 hours) after administration of the active agent.
  • the tissue can be any tissue that is in need of treatment with a subject method, e.g., a tissue that exhibits excessive NO production and/or elevated DDAH activity.
  • the tissue is lung tissue.
  • a target dosage of an active agent can be considered to be a dosage that provides for a sustained tissue concentration of the active agent of from about 3 ⁇ to about 5 ⁇ , 5 ⁇ to about 10 ⁇ , from about 10 ⁇ to about 15 ⁇ , from about 15 ⁇ to about 20 ⁇ , from about 20 ⁇ to about 25 ⁇ , from about 25 ⁇ to about 30 ⁇ , from about 30 ⁇ to about 35 ⁇ , from about 35 ⁇ to about 40 ⁇ , from about 40 ⁇ to about 50 ⁇ , from about 50 ⁇ to about 55 ⁇ , from about 55 ⁇ to about 60 ⁇ , from about 60 ⁇ to about 65 ⁇ , from about 65 ⁇ to about 70 ⁇ , from about 70 ⁇ to about 75 ⁇ , from about 75 ⁇ to about 80 ⁇ , from about 80 ⁇ to about 85
  • a "sustained" tissue concentration of an active agent refers to a concentration that is at least about 25%, at least about 30%, at least about 40%, or at least about 50% of the peak concentration, which concentration is maintained for a period of time of from about 1 hour to about 1.5 hours (hrs), from about 1.5 hrs to about 2 hours, from about 2 hours to about 4 hours, from about 4 hours to about 6 hours, from about 6 hours to about 8 hours, or from about 8 hours to about 12 hours, or more than 12 hours.
  • a target dosage of an active agent can be considered to be a dosage that provides for a sustained blood or plasma concentration of the active agent of greater than 3 ⁇ .
  • a target dosage of an active agent can be considered to be a dosage that provides for a sustained plasma concentration of the active agent of from about 3 ⁇ to about 100 ⁇ , or greater than 100 ⁇ , within a time period of from about 30 minutes to 120 hours (e.g., within a time period of from about 30 minutes to about 6 hours, from about 6 hours to about 12 hours, from about 12 hours to about 24 hours, from about 24 hours to about 48 hours, from about 48 hours to about 72 hours, from about 72 hours to about 96 hours, or from about 120 hours) after administration of the active agent.
  • a target dosage of an active agent can be considered to be a dosage that provides for a sustained blood or plasma concentration of the active agent of from about 3 ⁇ to about 5 ⁇ , 5 ⁇ to about 10 ⁇ , from about 10 ⁇ to about 15 ⁇ , from about 15 ⁇ to about 20 ⁇ , from about 20 ⁇ to about 25 ⁇ , from about 25 ⁇ to about 30 ⁇ , from about 30 ⁇ to about 35 ⁇ , from about 35 ⁇ to about 40 ⁇ , from about 40 ⁇ to about 50 ⁇ , from about 50 ⁇ to about 55 ⁇ , from about 55 ⁇ to about 60 ⁇ , from about 60 ⁇ to about 65 ⁇ , from about 65 ⁇ to about 70 ⁇ , from about 70 ⁇ to about 75 ⁇ , from about 75 ⁇ to about 80 ⁇ , from about 80 ⁇ to about 85 ⁇ , from about 85 ⁇ to about 90 ⁇ , from about 90 ⁇ to about 95 ⁇ , or from about 95 ⁇ to about 100 ⁇ , or greater than 100 ⁇ , within a time period of
  • a “sustained" blood or plasma concentration of an active agent refers to a concentration that is at least about 25%, at least about 30%, at least about 40%, or at least about 50% of the peak concentration, which concentration is maintained for a period of time of from about 1 hour to about 1.5 hours (hrs), from about 1.5 hrs to about 2 hours, from about 2 hours to about 4 hours, from about 4 hours to about 6 hours, from about 6 hours to about 8 hours, or from about 8 hours to about 12 hours, or more than 12 hours.
  • a target dosage of a compound of any one of Formulas la, lb, and Ic, as described above can be considered to be a dosage that provides for a sustained tissue concentration of the active agent of from about 3 ⁇ to about 5 ⁇ , 5 ⁇ to about 10 ⁇ , from about 10 ⁇ to about 100 ⁇ , from about 10 ⁇ to about 15 ⁇ , from about 15 ⁇ to about 20 ⁇ , from about 20 ⁇ to about 25 ⁇ , from about 25 ⁇ to about 30 ⁇ , from about 30 ⁇ to about 35 ⁇ , from about 35 ⁇ to about 40 ⁇ , from about 40 ⁇ to about 50 ⁇ , from about 50 ⁇ to about 55 ⁇ , from about 55 ⁇ to about 60 ⁇ , from about 60 ⁇ to about 65 ⁇ , from about 65 ⁇ to about 70 ⁇ , from about 70 ⁇ to about 75 ⁇ , from about 75 ⁇ to about 80 ⁇ , from about 80 ⁇ to about 85 ⁇ , from about 85 ⁇ to about 90 ⁇ ,
  • a target dosage of Omeprazole can be considered to be a dosage that provides for a sustained tissue concentration of Omeprazole of from about 3 ⁇ to about 5 ⁇ , 5 ⁇ to about 10 ⁇ , from about 10 ⁇ to about 100 ⁇ , from about 10 ⁇ to about 15 ⁇ , from about 15 ⁇ to about 20 ⁇ , from about 20 ⁇ to about 25 ⁇ , from about 25 ⁇ to about 30 ⁇ , from about 30 ⁇ to about 35 ⁇ , from about 35 ⁇ to about 40 ⁇ , from about 40 ⁇ to about 50 ⁇ , from about 50 ⁇ to about 55 ⁇ , from about 55 ⁇ to about 60 ⁇ , from about 60 ⁇ to about 65 ⁇ , from about 65 ⁇ to about 70 ⁇ , from about 70 ⁇ to about 75 ⁇ , from about 75 ⁇ to about 80 ⁇ , from about 80 ⁇ to about 85 ⁇ , from about 85 ⁇ to about 90 ⁇ , from about 90 ⁇ to about 95 ⁇ , or from about 95 ⁇ to
  • a suitable dosage range is one which provides from about 50 mg to about 100 mg of an active agent and can be administered in a single dose.
  • a target dosage of an active agent can be considered to be a dosage that provides for a concentration in the range of from about 3 ⁇ to about 100 ⁇ (or greater than 100 ⁇ ) in a sample of host blood drawn within the first 24-48 hours after administration of the agent.
  • a target dosage of an active agent can be considered to be a dosage that provides for a concentration, in blood, within the first 24-48 hours after administration of the active agent, in a range of from about 3 ⁇ to about 5 ⁇ , 5 ⁇ to about 10 ⁇ , from about 10 ⁇ to about 15 ⁇ , from about 15 ⁇ to about 20 ⁇ , from about 20 ⁇ to about 25 ⁇ , from about 25 ⁇ to about 30 ⁇ , from about 30 ⁇ to about 35 ⁇ , from about 35 ⁇ to about 40 ⁇ , from about 40 ⁇ to about 50 ⁇ , from about 50 ⁇ to about 55 ⁇ , from about 55 ⁇ to about 60 ⁇ , from about 60 ⁇ to about 65 ⁇ , from about 65 ⁇ to about 70 ⁇ , from about 70 ⁇ to about 75 ⁇ , from about 75 ⁇ to about 80 ⁇ , from about 80 ⁇ to about 85 ⁇ , from about 85 ⁇ to about 90 ⁇ , from about 90 ⁇ to about 95 ⁇ , or from about 95 ⁇ to
  • an active agent is administered via oral administration, and a target dosage of an active agent via oral administration is in a range that provides for a concentration, in blood, within about the first 24 hours to about 48 hours after administration of the agent, in a range of from about 3 ⁇ to about 5 ⁇ , 5 ⁇ to about 10 ⁇ , from about 10 ⁇ to about 15 ⁇ , from about 15 ⁇ to about 20 ⁇ , from about 20 ⁇ to about 25 ⁇ , from about 25 ⁇ to about 30 ⁇ , from about 30 ⁇ to about 35 ⁇ , from about 35 ⁇ to about 40 ⁇ , from about 40 ⁇ to about 50 ⁇ , from about 50 ⁇ to about 55 ⁇ , from about 55 ⁇ to about 60 ⁇ , from about 60 ⁇ to about 65 ⁇ , from about 65 ⁇ to about 70 ⁇ , from about 70 ⁇ to about 75 ⁇ , from about 75 ⁇ to about 80 ⁇ , from about 80 ⁇ to about 85 ⁇ , from about 85 ⁇ to about 90 ⁇ , from about 90
  • an active agent is administered via oral administration, and a target dosage of an active agent via oral administration is in a range that provides for a concentration, in blood, within about the first 24 hours to about 48 hours after administration of the agent, of greater than about 3 ⁇ .
  • an active agent is administered via an inhalational route of administration, and a target dosage of an active agent via an inhalational route administration is in a range that provides for a concentration, in blood and/or tissue (e.g., lung tissue), within about the first 24 hours to about 48 hours after administration of the agent, in a range of from about 3 ⁇ to about 5 ⁇ , 5 ⁇ to about 10 ⁇ , from about 10 ⁇ to about 15 ⁇ , from about 15 ⁇ to about 20 ⁇ , from about 20 ⁇ to about 25 ⁇ , from about 25 ⁇ to about 30 ⁇ , from about 30 ⁇ to about 35 ⁇ , from about 35 ⁇ to about 40 ⁇ , from about 40 ⁇ to about 50 ⁇ , from about 50 ⁇ to about 55 ⁇ , from about 55 ⁇ to about 60 ⁇ , from about 60 ⁇ to about 65 ⁇ , from about 65 ⁇ to about 70 ⁇ , from about 70 ⁇ to about 75 ⁇ , from about 75 ⁇ to about 80 ⁇ , from about 80
  • an active agent is administered via an inhalational route of administration, and a target dosage of an active agent via an inhalational route of administration is in a range that provides for a concentration, in blood and/or tissue (e.g., lung tissue), within about the first 24 hours to about 48 hours after administration of the agent, of greater than about 3 ⁇ .
  • tissue e.g., lung tissue
  • an active agent is administered via oral administration and an inhalational route of administration
  • a target dosage of an active agent via oral administration and an inhalational route of administration is in a range that provides for a concentration, in blood, within about the first 24 hours to about 48 hours after administration of the agent, in a range of from about 3 ⁇ to about 5 ⁇ , 5 ⁇ to about 10 ⁇ , from about 10 ⁇ to about 15 ⁇ , from about 15 ⁇ to about 20 ⁇ , from about 20 ⁇ to about 25 ⁇ , from about 25 ⁇ to about 30 ⁇ , from about 30 ⁇ to about 35 ⁇ , from about 35 ⁇ to about 40 ⁇ , from about 40 ⁇ to about 50 ⁇ , from about 50 ⁇ to about 55 ⁇ , from about 55 ⁇ to about 60 ⁇ , from about 60 ⁇ to about 65 ⁇ , from about 65 ⁇ to about 70 ⁇ , from about 70 ⁇ to about 75 ⁇ , from about 75 ⁇ to about 80 ⁇ , from about 80 ⁇ to about
  • an active agent is administered via oral administration and an inhalational route of administration
  • a target dosage of an active agent administered via oral administration and via an inhalational route of administration is in a range that provides for a concentration, in blood, within about the first 24 hours to about 48 hours after administration of the agent, of greater than about 3 ⁇ .
  • a dosage of a compound of any one of Formulas la, lb, and Ic, as described above can be considered to be a dosage that, when administered via oral administration, provides for an area under the curve (AUC) of greater than 2 ⁇ -hour/liter ( ⁇ -hr/L), greater than 3 ⁇ -hr/L, greater than 5 ⁇ -hr/L, greater than 10 ⁇ -hr/L, or greater than 15 ⁇ -hr/L, up to about 500 ⁇ -hr/L.
  • the AUC value can be determined after a single dose of the active agent, e.g., within about 24 hours (e.g., from about 1 minute to about 8 to 10 hours) after a single dose.
  • a dosage of Omeprazole can be considered to be a dosage that, when administered via oral administration, provides for an AUC value of greater than 3 ⁇ -hr/L, e.g., from about 3 ⁇ -hr/L to about 5 ⁇ -hr/L, from about 5 ⁇ -hr/L to about 10 ⁇ -hr/L, from about 10 ⁇ -hr/L to about 15 ⁇ -hr/L, from about 15 ⁇ -hr/L to about 20 ⁇ -hr/L, from about 20 ⁇ -hr/L to about 25 ⁇ -hr/L, from about 25 ⁇ -hr/L to about 30 ⁇ -hr/L, or greater than 30 ⁇ -hr/L.
  • a dosage of Lansoprazole can be considered to be a dosage that, when administered via oral administration, provides for an AUC value of greater than 5 ⁇ -hr/L, e.g., from about 5 ⁇ -hr/L to about 10 ⁇ -hr/L, from about 10 ⁇ -hr/L to about 15 ⁇ -hr/L, from about 15 ⁇ -hr/L to about 20 ⁇ -hr/L, from about 20 ⁇ -hr/L to about 25 ⁇ -hr/L, from about 25 ⁇ -hr/L to about 30 ⁇ -hr/L, from about 30 ⁇ -hr/L to about 40 ⁇ -hr/L, from about 40 ⁇ -hr/L to about 50 ⁇ -hr/L, or greater than 50 ⁇ -hr/L.
  • a dosage of Esomeprazole can be considered to be a dosage that, when administered via oral administration, provides for an AUC value of greater than 15 ⁇ -hr/L, e.g., from about 15 ⁇ -hr/L to about 20 ⁇ -hr/L, from about 20 ⁇ -hr/L to about 25 ⁇ -hr/L, from about 25 ⁇ -hr/L to about 30 ⁇ -hr/L, from about 30 ⁇ -hr/L to about 40 ⁇ -hr/L, from about 40 ⁇ -hr/L to about 50 ⁇ -hr/L, or greater than 50 ⁇ -hr/L.
  • a dosage of Rabeprazole can be considered to be a dosage that, when administered via oral administration, provides for an AUC value of greater than 2 ⁇ -hr/L, e.g., from about 2.5 ⁇ -hr/L to about 3 ⁇ -hr/L, from about 3 ⁇ -hr/L to about 5 ⁇ -hr/L, from about 5 ⁇ -hr/L to about 10 ⁇ -hr/L, from about from about 10 ⁇ -hr/L to about 15 ⁇ -hr/L, from about 15 ⁇ -hr/L to about 20 ⁇ -hr/L, from about 20 ⁇ -hr/L to about 25 ⁇ -hr/L, from about 25 ⁇ -hr/L to about 30 ⁇ -hr/L, from about 30 ⁇ -hr/L to about 40 ⁇ -hr/L, from about 40 ⁇ -hr/L to about 50 ⁇ -hr/L, or greater
  • a dosage of Pantoprazole can be considered to be a dosage that, when administered via oral administration, provides for an AUC value of greater than 10 ⁇ -hr/L, e.g., from about 10 ⁇ -hr/L to about 15 ⁇ -hr/L, from about 15 ⁇ -hr/L to about 20 ⁇ -hr/L, from about 20 ⁇ -hr/L to about 25 ⁇ -hr/L, from about 25 ⁇ -hr/L to about 30 ⁇ -hr/L, from about 30 ⁇ -hr/L to about 40 ⁇ -hr/L, from about 40 ⁇ -hr/L to about 50 ⁇ -hr/L, or greater than 50 ⁇ -hr/L.
  • a dosage of a compound of any one of Formulas la, lb, and Ic, as described above, can be considered to be a dosage that, when administered via intravenous
  • AUC area under the curve
  • a dosage of Omeprazole can be considered to be a dosage that, when administered via intravenous administration, provides for an AUC value of greater than 2.2 ⁇ -hr/L, e.g., from about 2.5 ⁇ -hr/L to about to about 3 ⁇ -hr/L, from about 3 ⁇ -hr/L to about 5 ⁇ - hr/L, from about 5 ⁇ -hr/L to about 10 ⁇ -hr/L, from about from about 10 ⁇ -hr/L to about 15 ⁇ -hr/L, from about 15 ⁇ -hr/L to about 20 ⁇ -hr/L, from about 20 ⁇ -hr/L to about 25 ⁇ -hr/L, from about 25 ⁇ -hr/L to about 30 ⁇ -hr/L, from about 30 ⁇ -hr/L to about 40 ⁇ -hr/L, from about 40 ⁇ -hr/L to about 50 ⁇ -hr/L,
  • a dosage of Lansoprazole can be considered to be a dosage that, when administered via intravenous administration, provides for an AUC value of greater than 9 ⁇ -hr/L, e.g., from about 9 ⁇ -hr/L to about 10 ⁇ -hr/L, from about from about 10 ⁇ -hr/L to about 15 ⁇ -hr/L, from about 15 ⁇ -hr/L to about 20 ⁇ -hr/L, from about 20 ⁇ -hr/L to about 25 ⁇ -hr/L, from about 25 ⁇ -hr/L to about 30 ⁇ -hr/L, from about 30 ⁇ -hr/L to about 40 ⁇ -hr/L, from about 40 ⁇ -hr/L to about 50 ⁇ -hr/L, or greater than 50 ⁇ -hr/L.
  • a dosage of Esomeprazole can be considered to be a dosage that, when administered via intravenous administration, provides for an AUC value of greater than 16 ⁇ -hr/L, e.g., from about 17 ⁇ -hr/L to about 20 ⁇ -hr/L, from about 20 ⁇ -hr/L to about 25 ⁇ -hr/L, from about 25 ⁇ -hr/L to about 30 ⁇ -hr/L, from about 30 ⁇ -hr/L to about 40 ⁇ -hr/L, from about 40 ⁇ -hr/L to about 50 ⁇ -hr/L, or greater than 50 ⁇ -hr/L.
  • a dosage of Rabeprazole can be considered to be a dosage that, when administered via intravenous administration, provides for an AUC value of greater than 5 ⁇ -hr/L, e.g., from about 5 ⁇ -hr/L to about 10 ⁇ -hr/L, from about 10 ⁇ -hr/L to about 15 ⁇ -hr/L, from about 15 ⁇ -hr/L to about 20 ⁇ -hr/L, from about 20 ⁇ -hr/L to about 25 ⁇ -hr/L, from about 25 ⁇ -hr/L to about 30 ⁇ -hr/L, from about 30 ⁇ -hr/L to about 40 ⁇ -hr/L, from about 40 ⁇ -hr/L to about 50 ⁇ -hr/L, or greater than 50 ⁇ -hr/L.
  • a dosage of Pantoprazole can be considered to be a dosage that, when administered via intravenous administration, provides for an AUC value of greater than 13 ⁇ -hr/L, e.g., from about 13 ⁇ -hr/L to about 15 ⁇ -hr/L, from about 15 ⁇ -hr/L to about 20 ⁇ -hr/L, from about 20 ⁇ -hr/L to about 25 ⁇ -hr/L, from about 25 ⁇ -hr/L to about 30 ⁇ -hr/L, from about 30 ⁇ -hr/L to about 40 ⁇ -hr/L, from about 40 ⁇ -hr/L to about 50 ⁇ -hr/L, or greater than 50 ⁇ -hr/L.
  • a dosage of a compound of any one of Formulas la, lb, and Ic, as described above can be considered to be a dosage that, when administered via oral administration, provides for a Cmax value of greater thanl.5 ⁇ , greater than 2.5 ⁇ , greater than 5 ⁇ , greater than 10 ⁇ , greater than 25 ⁇ , greater than 50 ⁇ , greater than 100 ⁇ , up to about 250 ⁇ , where Cmax is the mean peak plasma concentration.
  • a dosage of Omeprazole can be considered to be a dosage that, when administered via oral administration, provides for a C mj value of greater than 1.7 ⁇ , e.g., from about 1.8 ⁇ to about 2 ⁇ , from about 2 ⁇ to about 5 ⁇ , from about 5 ⁇ to about 10 ⁇ , from about 10 ⁇ to about 25 ⁇ , from about 25 ⁇ to about 50 ⁇ , from about 50 ⁇ to about 75 ⁇ , from about 75 ⁇ to about 100 ⁇ , from about 100 ⁇ to about 150 ⁇ , or greater than 150 ⁇ .
  • a dosage of Lansoprazole can be considered to be a dosage that, when administered via oral administration, provides for a C ⁇ value of greater than 2.5 ⁇ , e.g., from about 2.5 ⁇ to about 5 ⁇ , from about 5 ⁇ to about 10 ⁇ , from about 10 ⁇ to about 25 ⁇ , from about 25 ⁇ to about 50 ⁇ , from about 50 ⁇ to about 75 ⁇ , from about 75 ⁇ to about 100 ⁇ , from about 100 ⁇ to about 150 ⁇ , or greater than 150 ⁇ .
  • a dosage of Esomeprazole can be considered to be a dosage that, when administered via oral administration, provides for a C ⁇ value of greater than 5.2 ⁇ , e.g., from about 5.5 ⁇ to about 10 ⁇ , from about 10 ⁇ to about 25 ⁇ , from about 25 ⁇ to about 50 ⁇ , from about 50 ⁇ to about 75 ⁇ , from about 75 ⁇ to about 100 ⁇ , from about 100 ⁇ to about 150 ⁇ , or greater than 150 ⁇ .
  • a dosage of Rabeprazole can be considered to be a dosage that, when administered via oral administration, provides for a Cmax value of greater than 1.2 ⁇ , e.g., from about 1.5 ⁇ to about 1.75 ⁇ , from about 1.75 ⁇ to about 2 ⁇ , from about 2 ⁇ to about 5 ⁇ , from about 5 ⁇ to about 10 ⁇ , from about 10 ⁇ to about 25 ⁇ , from about 25 ⁇ to about 50 ⁇ , from about 50 ⁇ to about 75 ⁇ , from about 75 ⁇ to about 100 ⁇ , from about 100 ⁇ to about 150 ⁇ , or greater than 150 ⁇ .
  • a dosage of Pantoprazole can be considered to be a dosage that, when administered via oral administration, provides for a Cmax value of greater than 5.5 ⁇ , e.g., from about 5.6 ⁇ to about 6 ⁇ , from about 6 ⁇ to about 10 ⁇ , from about 10 ⁇ to about 25 ⁇ , from about 25 ⁇ to about 50 ⁇ , from about 50 ⁇ to about 75 ⁇ , from about 75 ⁇ to about 100 ⁇ , from about 100 ⁇ to about 150 ⁇ , or greater than 150 ⁇ .
  • a dosage of a compound of any one of Formulas la, lb, and Ic, as described above, can be considered to be a dosage that, when administered via intravenous
  • Cmax value of greater than 3.5 ⁇ , greater than 5 ⁇ , greater than 10 ⁇ , greater than 25 ⁇ , greater than 50 ⁇ , greater than 100 ⁇ , up to about 250 ⁇ , where C mj is the mean peak plasma concentration.
  • a dosage of Lansoprazole can be considered to be a dosage that, when administered via oral administration, provides for a Cmax value of greater than 4.6 ⁇ , e.g., from about 4.7 ⁇ to about 5 ⁇ , from about 5 ⁇ to about 7.5 ⁇ , from about 7.5 ⁇ to about 10 ⁇ , from about 10 ⁇ to about 25 ⁇ , from about 25 ⁇ to about 50 ⁇ , from about 50 ⁇ to about 75 ⁇ , from about 75 ⁇ to about 100 ⁇ , from about 100 ⁇ to about 150 ⁇ , or greater than 150 ⁇ .
  • a dosage of Omeprazole can be considered to be a dosage that, when administered via oral administration, provides for a Cmax value of greater than 3.3 ⁇ , e.g., from about 3.5 ⁇ to about 4 ⁇ , from about 4 ⁇ to about 5 ⁇ , from about 5 ⁇ to about 7.5 ⁇ , from about 7.5 ⁇ to about 10 ⁇ , from about 10 ⁇ to about 25 ⁇ , from about 25 ⁇ to about 50 ⁇ , from about 50 ⁇ to about 75 ⁇ , from about 75 ⁇ to about 100 ⁇ , from about 100 ⁇ to about 150 ⁇ , or greater than 150 ⁇ .
  • a dosage of Esomeprazole can be considered to be a dosage that, when administered via oral administration, provides for a Cmax value of greater than 7.5 ⁇ , e.g., from about 7.6 ⁇ to about 8 ⁇ , from about 8 ⁇ to about 10 ⁇ , from about 10 ⁇ to about 25 ⁇ , from about 25 ⁇ to about 50 ⁇ , from about 50 ⁇ to about 75 ⁇ , from about 75 ⁇ to about 100 ⁇ , from about 100 ⁇ to about 150 ⁇ , or greater than 150 ⁇ .
  • a dosage of Rabeprazole can be considered to be a dosage that, when administered via oral administration, provides for a Cmax value of greater than 3.4 ⁇ , e.g., from about 3.5 ⁇ to about 4 ⁇ , from about 4 ⁇ to about 5 ⁇ , from about 5 ⁇ to about 7.5 ⁇ , from about 7.5 ⁇ to about 10 ⁇ , from about 10 ⁇ to about 25 ⁇ , from about 25 ⁇ to about 50 ⁇ , from about 50 ⁇ to about 75 ⁇ , from about 75 ⁇ to about 100 ⁇ , from about 100 ⁇ to about 150 ⁇ , or greater than 150 ⁇ .
  • a dosage of Pantoprazole can be considered to be a dosage that, when administered via oral administration, provides for a Cmax value of greater than 12.8 ⁇ , e.g., from about 13 ⁇ to about 14 ⁇ , from about 14 ⁇ to about 15 ⁇ , from about 15 ⁇ to about 20 ⁇ , from about 20 ⁇ to about 25 ⁇ , from about 25 ⁇ to about 50 ⁇ , from about 50 ⁇ to about 75 ⁇ , from about 75 ⁇ to about 100 ⁇ , from about 100 ⁇ to about 150 ⁇ , or greater than 150 ⁇ .
  • a dosage of a compound of any one of Formulas la, lb, and Ic, as described above can be considered to be a dosage that, when administered via an inhalational administration, provides for an AUC value of greater than 2 ⁇ -hour/liter ( ⁇ -hr/L), greater than 3 ⁇ -hr/L, greater than 5 ⁇ -hr/L, greater than 10 ⁇ -hr/L, or greater than 15 ⁇ -hr/L, up to about 500 ⁇ -hr/L, where the AUC value is determined after a single dose of the active agent, e.g., within about 24 hours (e.g., from about 1 minute to about 8 to 10 hours) after a single dose.
  • a dosage of a compound of any one of Formulas la, lb, and Ic e.g.,
  • Omeprazole, Lansoprazole, Esomeprazole, Rabeprazole, Pantoprazole, or Tenatoprazole), as described above, can be considered to be a dosage that, when administered via an inhalational administration, provides for an AUC value of from about from about 3 ⁇ -hr/L to about 5 ⁇ -hr/L, from about 5 ⁇ -hr/L to about 10 ⁇ -hr/L, from about 10 ⁇ -hr/L to about 15 ⁇ -hr/L, from about 15 ⁇ -hr/L to about 20 ⁇ -hr/L, from about 20 ⁇ -hr/L to about 25 ⁇ -hr/L, from about 25 ⁇ -hr/L to about 30 ⁇ -hr/L, from about 30 ⁇ -hr/L to about 40 ⁇ -hr/L, from about 40 ⁇ -hr/L to about 50 ⁇ -hr/L, or greater than 50 ⁇ -hr/L.
  • a dosage of a compound of any one of Formulas la, lb, and Ic, as described above can be considered to be a dosage that, when administered via an inhalational route of administration, provides for a Cmax value of greater thanl.5 ⁇ , greater than 2.5 ⁇ , greater than 5 ⁇ , greater than 10 ⁇ , greater than 25 ⁇ , greater than 50 ⁇ , greater than 100 ⁇ , up to about 250 ⁇ , where Cmax is the mean peak plasma concentration.
  • a dosage of a compound of any one of Formulas la, lb, and Ic can be considered to be a dosage that, when administered via an inhalational administration, provides for a Cmax value of from about 1.5 ⁇ to about 2 ⁇ , from about 2 ⁇ to about 2.5 ⁇ , from about 2.5 ⁇ to about 3 ⁇ , from about 3 ⁇ to about 3.5 ⁇ , from about 3.5 ⁇ to about 4 ⁇ , from about 4 ⁇ to about 5 ⁇ , from about 5 ⁇ to about 7.5 ⁇ , from about 7.5 ⁇ to about 10 ⁇ , from about 10 ⁇ to about 25 ⁇ , from about 25 ⁇ to about 50 ⁇ , from about 50 ⁇ to about 75 ⁇ , from about 75 ⁇ to about 100 ⁇ , from about 100 ⁇ to about 150 ⁇ , or greater
  • An active agent can be administered at a first dosage for a first period of time, and a second dosage for a second period of time.
  • an active agent can be administered at a first dosage for a first period of time, and a second dosage for a second period of time, where the second dosage is lower than the first dosage, e.g., where the second dosage is from about 90% to about 80%, from about 80% to about 70%, from about 70% to about 60%, from about 60% to about 50%, or from about 50% to about 25%, of the first dosage.
  • the first period of time can be 1 day, or can be more than 1 day (e.g., the first period of time can be from 1 day to 2 days, from 2 days to 3 days or more than 3 days); and the second period of time can be from 1 day to 2 days, from 2 days to 3 days, from 3 days to 1 week, or more than 1 week.
  • the first period of time is 1 day; and the second period of time can be from 1 day to 2 days, from 2 days to 3 days, from 3 days to 1 week, or more than 1 week.
  • an active agent is formulated for oral delivery to an individual in need of such an agent.
  • a compound of any one of Formulas la, lb, and Ic e.g.,
  • Omeprazole, Lansoprazole, Esomeprazole, Rabeprazole, Pantoprazole, or Tenatoprazole), as described above, is formulated to protect the pro-drug form from conversion to the sulfenic acid form, where such conversion can occur by action of components of gastric fluid, e.g., gastric enzymes.
  • gastric fluid e.g., gastric enzymes.
  • a compound of any one of Formulas la, lb, and Ic e.g., Omeprazole, Lansoprazole, Esomeprazole, Rabeprazole, Pantoprazole, or Tenatoprazole
  • an enteric coating is formulated with an enteric coating.
  • Suitable enteric coatings include, e.g., polymethacrylates (e.g., methacrylic acid/ethyl acrylate); cellulose esters (e.g., cellulose acetate phthalate (CAP); cellulose acetate trimellitate (CAT); hydroxypropyl methylcellulose acetate succinate (HPMCAS)); polyvinyl derivatives (e.g., polyvinyl acetate phthalate (PVAP)); and the like. Additional enteric coatings that are suitable for use are decribed below.
  • polymethacrylates e.g., methacrylic acid/ethyl acrylate
  • cellulose esters e.g., cellulose acetate phthalate (CAP); cellulose acetate trimellitate (CAT); hydroxypropyl methylcellulose acetate succinate (HPMCAS)
  • PVAP polyvinyl derivatives
  • a formulation comprising an active agent will in some embodiments include an enteric-soluble coating material.
  • Suitable enteric-soluble coating material include hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methyl cellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), polyvinyl phthalic acetate (PVPA), EudragitTM, and shellac.
  • an active agent is formulated with one or more pharmaceutical excipients and coated with an enteric coating, as described in U.S. Patent No. 6,346,269.
  • a solution comprising an active agent and a stabilizer is coated onto a core comprising pharmaceutically acceptable excipients, to form an active agent-coated core; a sub- coating layer is applied to the active agent-coated core, which is then coated with an enteric coating layer.
  • the core generally includes pharmaceutically inactive components such as lactose, a starch, mannitol, sodium carboxymethyl cellulose, sodium starch glycolate, sodium chloride, potassium chloride, pigments, salts of alginic acid, talc, titanium dioxide, stearic acid, stearate, micro-crystalline cellulose, glycerin, polyethylene glycol, triethyl citrate, tributyl citrate, propanyl triacetate, dibasic calcium phosphate, tribasic sodium phosphate, calcium sulfate, cyclodextrin, and castor oil.
  • Suitable solvents for an active agent include aqueous solvents.
  • Suitable stabilizers include alkali-metals and alkaline earth metals, bases of phosphates and organic acid salts and organic amines.
  • the sub-coating layer comprises one or more of an adhesive, a plasticizer, and an anti-tackiness agent.
  • Suitable anti- tackiness agents include talc, stearic acid, stearate, sodium stearyl fumarate, glyceryl behenate, kaolin and aerosil.
  • Suitable adhesives include polyvinyl pyrrolidone (PVP), gelatin, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), vinyl acetate (VA), polyvinyl alcohol (PVA), methyl cellulose (MC), ethyl cellulose (EC), hydroxypropyl methyl cellulose phthalate (HPMCP), cellulose acetate phthalates (CAP), xanthan gum, alginic acid, salts of alginic acid, EudragitTM, copolymer of methyl acrylic acid/methyl methacrylate with polyvinyl acetate phthalate (PVAP).
  • PVAP polyvinyl pyrrolidone
  • gelatin gelatin
  • HEC hydroxyethyl cellulose
  • HPC hydroxypropyl cellulose
  • HPMC hydroxypropyl methyl cellulose
  • VA vinyl acetate
  • PVA polyvinyl alcohol
  • MC methyl
  • Suitable plasticizers include glycerin, polyethylene glycol, triethyl citrate, tributyl citrate, propanyl triacetate and castor oil.
  • Suitable enteric-soluble coating material include hydroxypropyl methylcellulose acetate succinate (HPMC AS), hydroxypropyl methyl cellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), polyvinyl phthalic acetate (PVPA), EudragitTM and shellac.
  • Suitable oral formulations also include an active agent formulated with any of the following: microgranules (see, e.g., U.S. Patent No. 6,458,398); biodegradable macromers (see, e.g., U.S. Patent No. 6,703,037); biodegradable hydrogels (see, e.g., Graham and McNeill (1989)
  • bioabsorbable lactone polymers see, e.g., U.S. Patent No. 5,631,015
  • slow release protein polymers see, e.g., U.S. Patent No. 6,699,504; Pelias Technologies, Inc.
  • a poly(lactide-co- glycolide/polyethylene glycol block copolymer see, e.g., U.S. Patent No. 6,630,155; Atrix
  • composition comprising a biocompatible polymer and particles of metal cation- stabilized agent dispersed within the polymer (see, e.g., U.S. Patent No. 6,379,701; Alkermes
  • Controlled Therapeutics, Inc. and microspheres (see, e.g., U.S. Patent No. 6,303,148; Octoplus, B.V.).
  • Suitable oral formulations also include an active agent formulated with any of the following: a carrier such as Emisphere® (Emisphere Technologies, Inc.); TIMERx, a hydrophilic matrix combining xanthan and locust bean gums which, in the presence of dextrose, form a strong binder gel in water (Penwest); GeminexTM (Pen west); ProciseTM (GlaxoSmithKline); SAVITTM (Mistral Pharma Inc.); RingCapTM (Alza Corp.); Smartrix® (Smartrix Technologies, Inc.); SQZgelTM
  • a carrier such as Emisphere® (Emisphere Technologies, Inc.); TIMERx, a hydrophilic matrix combining xanthan and locust bean gums which, in the presence of dextrose, form a strong binder gel in water (Penwest); GeminexTM (Pen west); ProciseTM (GlaxoSmithKline); SAVITTM (Mistral Pharma Inc.);
  • formulations such as those described in U.S. Patent No. 6,296,842 (Alkermes Controlled Therapeutics, Inc.); U.S. Patent No. 6,187,330 (Scios, Inc.); and the like.
  • Suitable intestinal absorption enhancers include, but are not limited to, calcium chelators (e.g., citrate, ethylenediamine tetracetic acid); surfactants (e.g., sodium dodecyl sulfate, bile salts, palmitoylcarnitine, and sodium salts of fatty acids); toxins (e.g., zonula occludens toxin); and the like.
  • calcium chelators e.g., citrate, ethylenediamine tetracetic acid
  • surfactants e.g., sodium dodecyl sulfate, bile salts, palmitoylcarnitine, and sodium salts of fatty acids
  • toxins e.g., zonula occludens toxin
  • an active agent is formulated in a controlled release formulation.
  • Controlled release within the scope of this invention can be taken to mean any one of a number of extended release dosage forms.
  • the following terms may be considered to be substantially equivalent to controlled release, for the purposes of the present invention: continuous release, controlled release, delayed release, depot, gradual release, long-term release, programmed release, prolonged release, proportionate release, protracted release, repository, retard, slow release, spaced release, sustained release, time coat, timed release, delayed action, extended action, layered-time action, long acting, prolonged action, repeated action, slowing acting, sustained action, sustained-action medications, and extended release. Further discussions of these terms may be found in Lesczek Krowczynski, Extended-Release Dosage Forms, 1987 (CRC Press, Inc.).
  • Controlled release technologies cover a very broad spectrum of drug dosage forms. Controlled release technologies include, but are not limited to physical systems and chemical systems.
  • Physical systems include, but are not limited to, reservoir systems with rate-controlling membranes, such as microencapsulation, macroencapsulation, and membrane systems; reservoir systems without rate-controlling membranes, such as hollow fibers, ultra microporous cellulose triacetate, and porous polymeric substrates and foams; monolithic systems, including those systems physically dissolved in non-porous, polymeric, or elastomeric matrices (e.g., nonerodible, erodible, environmental agent ingression, and degradable), and materials physically dispersed in non-porous, polymeric, or elastomeric matrices (e.g., nonerodible, erodible, environmental agent ingression, and degradable); laminated structures, including reservoir layers chemically similar or dissimilar to outer control layers; and other physical methods, such as osmotic pumps, or adsorption onto ion-exchange resins.
  • rate-controlling membranes such as microencapsulation, macroencapsulation, and membrane systems
  • Chemical systems include, but are not limited to, chemical erosion of polymer matrices (e.g., heterogeneous, or homogeneous erosion), or biological erosion of a polymer matrix (e.g., heterogeneous, or homogeneous). Additional discussion of categories of systems for controlled release may be found in Agis F. Kydonieus, Controlled Release Technologies: Methods, Theory and
  • controlled release drug formulations that are developed for oral administration. These include, but are not limited to, osmotic pressure -controlled gastrointestinal delivery systems; hydrodynamic pressure-controlled gastrointestinal delivery systems; membrane permeation-controlled gastrointestinal delivery systems, which include microporous membrane permeation-controlled gastrointestinal delivery devices; gastric fluid-resistant intestine targeted controlled-release gastrointestinal delivery devices; gel diffusion-controlled gastrointestinal delivery systems; and ion-exchange-controlled gastrointestinal delivery systems, which include cationic and anionic drugs. Additional information regarding controlled release drug delivery systems may be found in Yie W. Chien, Novel Drug Delivery Systems, 1992 (Marcel Dekker, Inc.). Some of these formulations will now be discussed in more detail.
  • Enteric coatings are applied to tablets to prevent the release of drugs in the stomach either to reduce the risk of unpleasant side effects or to maintain the stability of the drug which might otherwise be subject to degradation of expose to the gastric environment.
  • Most polymers that are used for this purpose are polyacids that function by virtue or the fact that their solubility in aqueous medium is pH-dependent, and they require conditions with a pH higher than normally encountered in the stomach.
  • enteric coating of a solid or liquid dosage form is enteric coating of a solid or liquid dosage form.
  • the enteric coatings are designed to disintegrate in intestinal fluid for ready absorption. Delay of absorption of the active agent that is incorporated into a formulation with an enteric coating is dependent on the rate of transfer through the gastrointestinal tract, and so the rate of gastric emptying is an important factor.
  • an active agent can be contained in an enterically coated multiple -unit dosage form.
  • a dosage form comprising an active agent is prepared by spray-coating granules of the active agent-enteric coating agent solid dispersion on an inert core material. These granules can result in prolonged absorption of the active agent with good bioavailability.
  • Typical enteric coating agents include, but are not limited to,
  • a solid dispersion may be defined as a dispersion of one or more active ingredients in an inert carrier or matrix in the solid state prepared by the melting (fusion), solvent, or melting-solvent method.
  • the selection of the carrier may have an influence on the dissolution characteristics of the dispersed active agent because the dissolution rate of a component from a surface may be affected by other components in a multiple component mixture.
  • a water-soluble carrier may result in a fast release of the drug from the matrix, or a poorly soluble or insoluble carrier may lead to a slower release of the drug from the matrix.
  • the solubility of an active agent may also be increased owing to some interaction with the carriers.
  • Examples of carriers useful in solid dispersions include, but are not limited to, water- soluble polymers such as polyethylene glycol, polyvinylpyrrolidone, and hydroxypropylmethyl - cellulose.
  • Alternative carriers include phosphatidylcholine. Phosphatidylcholine is an amphoteric but water-insoluble lipid, which may improve the solubility of otherwise insoluble active agents in an amorphous state in phosphatidylcholine solid dispersions.
  • Other carriers include polyoxyethylene hydrogenated castor oil. Poorly water-soluble active agents may be included in a solid dispersion system with an enteric polymer such as
  • Another solid dispersion dosage form includes incorporation of an active agent with ethyl cellulose and stearic acid in different ratios.
  • Another controlled release dosage form is a complex between an ion exchange resin and an active agent.
  • Ion exchange resin-drug complexes have been used to formulate sustained-release products of acidic and basic drugs.
  • a polymeric film coating is provided to the ion exchange resin-drug complex particles, making drug release from these particles diffusion controlled. See Y. Raghunathan et al., Sustained-release drug delivery system I: Coded ion-exchange resin systems for phenylpropanolamine and other drugs, J. Pharm. Sciences 70: 379-384 (1981).
  • Injectable microspheres are another controlled release dosage form.
  • Injectable micro spheres may be prepared by non-aqueous phase separation techniques, and spray-drying techniques.
  • Microspheres may be prepared using polylactic acid or copoly(lactic/glycolic acid).
  • Shigeyuki Takada Utilization of an Amorphous Form of a Water-Soluble GPIIb/IIIa Antagonist for Controlled Release From Biodegradable Micro spheres, Pharm. Res. 14: 1146-1150 (1997), and ethyl cellulose, Yoshiyuki Koida, Studies on Dissolution Mechanism of Drugs from Ethyl Cellulose Microcapsules, Chem. Pharm. Bull. 35: 1538-1545 (1987).
  • SODAS Spheroidal Oral Drug Absorption System
  • INDAS Insoluble Drug Absorption System
  • IPDAS Intestinal Protective Drug Absorption System
  • MOD AS Multiporous Oral Drug Absorption System
  • EFVAS Effervescent Drug Absorption System
  • PRODAS Programmable Oral Drug Absorption System
  • DUREDAS Dual Release Drug Absorption System
  • SODAS are multi particulate dosage forms utilizing controlled release beads.
  • INDAS are a family of drug delivery technologies designed to increase the solubility of poorly soluble drugs.
  • IPDAS are multi particulate tablet formation utilizing a combination of high density controlled release beads and an immediate -release granulate.
  • MOD AS are controlled release single unit dosage forms. Each tablet consists of an inner core surrounded by a semipermeable multiparous membrane that controls the rate of drug release.
  • EFVAS is an effervescent drug absorption system.
  • PRODAS is a family of multi particulate formulations utilizing combinations of immediate release and controlled release mini-tablets.
  • DUREDAS is a bilayer tablet formulation providing dual release rates within the one dosage form.
  • INDAS was developed specifically to improve the solubility and absorption characteristics of poorly water soluble drugs. Solubility and, in particular, dissolution within the fluids of the gastrointestinal tract is a key factor in determining the overall oral bioavailability of poorly water soluble drug. By enhancing solubility, one can increase the overall bioavailability of a drug with resulting reductions in dosage.
  • INDAS takes the form of a high energy matrix tablet, production of which is comprised of two distinct steps: the drug in question is converted to an amorphous form through a combination of energy, excipients, and unique processing procedures.
  • the resultant high energy complex may be stabilized by an absorption process that utilizes a novel polymer cross-linked technology to prevent recrystallization.
  • the combination of the change in the physical state of an active agent coupled with the solubilizing characteristics of the excipients employed enhances the solubility of the active agent.
  • the resulting absorbed amorphous drug complex granulate may be formulated with a gel-forming erodible tablet system to promote substantially smooth and continuous absorption.
  • IPDAS is a multi-particulate tablet technology that may enhance the gastrointestinal tolerability of potential irritant and ulcerogenic drugs. Intestinal protection is facilitated by the multiparticulate nature of the IPDAS formulation which promotes dispersion of an irritant lipoate throughout the gastrointestinal tract. Controlled release characteristics of the individual beads may avoid high concentration of drug being both released locally and absorbed systemically. The combination of both approaches serves to minimize the potential harm of an active agent with resultant benefits to patients.
  • IPDAS is composed of numerous high density controlled release beads. Each bead may be manufactured by a two-step process that involves the initial production of a micromatrix with embedded active agent and the subsequent coating of this micromatrix with polymer solutions that form a rate -limiting semipermeable membrane in vivo. Once an IPDAS tablet is ingested, it may disintegrate and liberate the beads in the stomach. These beads may subsequently pass into the duodenum and along the gastrointestinal tract, e.g., in a controlled and gradual manner, independent of the feeding state. Release of the active agent occurs by diffusion process through the micromatrix and subsequently through the pores in the rate controlling semipermeable membrane.
  • the release rate from the IPDAS tablet may be customized to deliver a drug-specific absorption profile associated with optimized clinical benefit. Should a fast onset of activity be necessary, immediate release granulate may be included in the tablet. The tablet may be broken prior to administration, without substantially compromising drug release, if a reduced dose is required for individual titration.
  • MOD AS is a drug delivery system that may be used to control the absorption of water soluble agents.
  • Physically MOD AS is a non-disintegrating table formulation that manipulates drug release by a process of rate limiting diffusion by a semipermeable membrane formed in vivo. The diffusion process essentially dictates the rate of presentation of drug to the gastrointestinal fluids, such that the uptake into the body is controlled. Because of the minimal use of excipients, MOD AS can readily accommodate small dosage size forms.
  • Each MOD AS tablet begins as a core containing active drug plus excipients. This core is coated with a solution of insoluble polymers and soluble excipients.
  • the fluid of the gastrointestinal tract may dissolve the soluble excipients in the outer coating leaving substantially the insoluble polymer.
  • What results is a network of tiny, narrow channels connecting fluid from the gastrointestinal tract to the inner drug core of water soluble drug. This fluid passes through these channels, into the core, dissolving the drug, and the resultant solution of drug may diffuse out in a controlled manner. This may permit both controlled dissolution and absorption.
  • An advantage of this system is that the drug releasing pores of the tablet are distributed over substantially the entire surface of the tablet. This facilitates uniform drug absorption reduces aggressive unidirectional drug delivery.
  • MOD AS represents a very flexible dosage form in that both the inner core and the outer semipermeable membrane may be altered to suit the individual delivery requirements of a drug.
  • the addition of excipients to the inner core may help to produce a microenvironment within the tablet that facilitates more predictable release and absorption rates.
  • the addition of an immediate release outer coating may allow for development of combination products.
  • PROD AS may be used to deliver an active agent.
  • PROD AS is a multi particulate drug delivery technology based on the production of controlled release mini tablets in the size range of 1.5 to 4 mm in diameter.
  • the PROD AS technology is a hybrid of multi particulate and hydrophilic matrix tablet approaches, and may incorporate, in one dosage form, the benefits of both these drug delivery systems.
  • PROD AS involves the direct compression of an immediate release granulate to produce individual mini tablets that contain an active agent. These mini tablets are subsequently incorporated into hard gels and capsules that represent the final dosage form.
  • a more beneficial use of this technology is in the production of controlled release formulations.
  • the incorporation of various polymer combinations within the granulate may delay the release rate of drugs from each of the individual mini tablets.
  • These mini tablets may subsequently be coated with controlled release polymer solutions to provide additional delayed release properties. The additional coating may be necessary in the case of highly water soluble drugs or drugs that are perhaps gastroirritants where release can be delayed until the formulation reaches more distal regions of the gastrointestinal tract.
  • PROD AS technology lies in the inherent flexibility to formulation whereby combinations of mini tablets, each with different release rates, are incorporated into one dosage form. As well as potentially permitting controlled absorption over a specific period, this also may permit targeted delivery of drug to specific sites of absorption throughout the gastrointestinal tract. Combination products also may be possible using mini tablets formulated with different active ingredients.
  • DUREDAS is a bilayer tableting technology that may be used to an active agent.
  • DUREDAS was developed to provide for two different release rates, or dual release of a drug from one dosage form.
  • the term bilayer refers to two separate direct compression events that take place during the tableting process.
  • an immediate release granulate is first compressed, being followed by the addition of a controlled release element which is then compressed onto this initial tablet. This may give rise to the characteristic bilayer seen in the final dosage form.
  • the controlled release properties may be provided by a combination of hydrophilic polymers.
  • a rapid release of an active agent may be desirable in order to facilitate a fast onset of therapeutic effect.
  • one layer of the tablet may be formulated as an immediate release granulate.
  • the second layer of the tablet may release the drug in a controlled manner, e.g., through the use of hydrophilic polymers. This controlled release may result from a combination of diffusion and erosion through the hydrophilic polymer matrix.
  • a further extension of DUREDAS technology is the production of controlled release combination dosage forms.
  • two different active agents may be incorporated into the bilayer tablet and the release of drug from each layer controlled to maximize therapeutic effect of the combination.
  • An active agent can be incorporated into any one of the aforementioned controlled released dosage forms, or other conventional dosage forms.
  • the amount of active agent contained in each dose can be adjusted, to meet the needs of the individual patient, and the indication.
  • One of skill in the art and reading this disclosure will readily recognize how to adjust the level of an active agent and the release rates in a controlled release formulation, in order to optimize delivery of the active agent and its bioavailability.
  • An active agent will in some embodiments be administered to a patient by means of a pharmaceutical delivery system for the inhalation route.
  • An active agent may be formulated in a form suitable for administration by inhalation.
  • the inhalational route of administration provides the advantage that the inhaled drug can directly target the lung.
  • An inhalational pharmaceutical delivery system is one that is suitable for respiratory therapy by delivery of an active agent to mucosal linings of the bronchi.
  • This invention can utilize a system that depends on the power of a compressed gas to expel an active agent from a container.
  • An aerosol or pressurized package can be employed for this purpose.
  • the term "aerosol" is used in its conventional sense as referring to very fine liquid or solid particles carries by a propellant gas under pressure to a site of therapeutic application.
  • the aerosol contains an active agent, which can be dissolved, suspended, or emulsified in a mixture of a fluid carrier and a propellant.
  • the aerosol can be in the form of a solution, suspension, emulsion, powder, or semi-solid preparation. Aerosols employed in the present invention are intended for administration as fine, solid particles or as liquid mists via the respiratory tract of a patient.
  • propellants include, but are not limited to, hydrocarbons or other suitable gas.
  • the dosage unit may be determined by providing a value to deliver a metered amount.
  • An active agent can also be formulated for delivery with a nebulizer, which is an instrument that generates very fine liquid particles of substantially uniform size in a gas.
  • a nebulizer which is an instrument that generates very fine liquid particles of substantially uniform size in a gas.
  • a liquid containing an active agent is dispersed as droplets.
  • the small droplets can be carried by a current of air through an outlet tube of the nebulizer. The resulting mist penetrates into the respiratory tract of the patient.
  • a powder composition containing an active agent, with or without a lubricant, carrier, or propellant can be administered to a mammal in need of therapy.
  • This embodiment of the invention can be carried out with a conventional device for administering a powder pharmaceutical composition by inhalation.
  • a powder mixture of the compound and a suitable powder base such as lactose or starch may be presented in unit dosage form in for example capsular or cartridges, e.g. gelatin, or blister packs, from which the powder may be administered with the aid of an inhaler.
  • an active agent can be formulated in basically three different types of formulations for inhalation.
  • an active agent can be formulated with low boiling point propellants.
  • Such formulations are generally administered by conventional meter dose inhalers (MDI's).
  • MDI's can be modified so as to increase the ability to obtain repeatable dosing by utilizing technology which measures the inspiratory volume and flow rate of the patient as discussed within U.S. Patents 5,404,871 and 5,542,410.
  • an active agent can be formulated in aqueous or ethanolic solutions and delivered by conventional nebulizers.
  • an active agent can be formulated into dry powder formulations. Such formulations can be administered by simply inhaling the dry powder formulation after creating an aerosol mist of the powder.
  • a compound of any one of Formulas I-X is present in a unit dosage form in an amount of from about 10 mg to about 50 mg, e.g., from about 10 mg to about 15 mg, from about 15 mg to about 20 mg, from about 20 mg to about 25 mg, from about 25 mg to about 30 mg, from about 30 mg to about 35 mg, from about 35 mg to about 40 mg, from about 40 mg to about 45 mg, or from about 45 mg to about 50 mg.
  • a compound of any one of Formulas I-X is present in a unit dosage form in an amount of from about 50 mg to about 500 mg.
  • a compound of any one of Formulas I-X is present in a unit dosage form in an amount of from about 50 mg to about 60 mg, from about 60 mg to about 70 mg, from about 70 mg to about 80 mg, from about 80 mg to about 90 mg, from about 90 mg to about 100 mg, from about 90 mg to about 100 mg from about 100 mg to about 150 mg, from about 150 mg to about 175 mg, from about 175 mg to about 200 mg, from about 200 mg to about 250 mg, from about 250 mg to about 300 mg, from about 300 mg to about 350 mg, from about 350 mg to about 400 mg, from about 400 mg to about 450 mg, or from about 450 mg to about 500 mg.
  • an active agent is administered in an amount of from about 10 mg per day to about 100 mg/day, e.g., from about 10 mg/day to about 20 mg/day, from about 20 mg/day to about 30 mg/day, from about 30 mg/day to about 40 mg/day, from about 40 mg/day to about 50 mg/day, from about 50 mg/day to about 60 mg/day, from about 60 mg/day to about 70 mg/day, from about 70 mg/day to about 80 mg/day, from about 80 mg/day to about 90 mg/day, or from about 90 mg/day to about 100 mg/day.
  • an active agent is administered in an amount greater than 100 mg per day, e.g., where the total daily dosage is greater than 100 mg.
  • an active agent can be administered in an amount of from about 100 mg/day to about 150 mg/day, from about 150 mg/day to about 200 mg/day, from about 200 mg/day to about 250 mg/day, from about 250 mg/day to about 300 mg/day, from about 300 mg/day to about 350 mg/day, from about 400 mg/day to about 425 mg/day, from about 425 mg/day to about 450 mg/day, from about 450 mg/day to about 500 mg/day, from about 500 mg/day to about 550 mg/day, from about 550 mg/day to about 600 mg/day, from about 600 mg/day to about 650 mg/day, from about 650 mg/day to about 700 mg/day, from about 700 mg/day to about 750 mg/day, from about 750 mg/day to about 800 mg/day, from about 800 mg/
  • an active agent can be administered in an amount of from about 100 mg/day to about 250 mg/day, from about 250 mg/day to about 500 mg/day, from about 500 mg/day to about 1000 mg/day, from about 1000 mg/day to about 1500 mg/day, from about 1500 mg/day to about 2000 mg/day, or from about 2000 mg/day to about 2500 mg/day.
  • a target dosage of an active agent can be considered to be a dosage that provides for a sustained blood and/or tissue concentration of the active agent of greater than 3 ⁇ .
  • a target dosage of an active agent can be considered to be a dosage that provides for a sustained blood and/or tissue concentration of the active agent of from about 3 ⁇ to about 100 ⁇ , or greater than 100 ⁇ , within a time period of from about 30 minutes to 120 hours (e.g., within a time period of from about 30 minutes to about 6 hours, from about 6 hours to about 12 hours, from about 12 hours to about 24 hours, from about 24 hours to about 48 hours, from about 48 hours to about 72 hours, from about 72 hours to about 96 hours, or from about 120 hours) after administration of the active agent.
  • a target dosage of an active agent can be considered to be a dosage that provides for a sustained blood and/or tissue concentration of the active agent of from about 3 ⁇ to about 5 ⁇ , 5 ⁇ to about 10 ⁇ , from about 10 ⁇ to about 15 ⁇ , from about 15 ⁇ to about 20 ⁇ , from about 20 ⁇ to about 25 ⁇ , from about 25 ⁇ to about 30 ⁇ , from about 30 ⁇ to about 35 ⁇ , from about 35 ⁇ to about 40 ⁇ , from about 40 ⁇ to about 50 ⁇ , from about 50 ⁇ to about 55 ⁇ , from about 55 ⁇ to about 60 ⁇ , from about 60 ⁇ to about 65 ⁇ , from about 65 ⁇ to about 70 ⁇ , from about 70 ⁇ to about 75 ⁇ , from about 75 ⁇ to about 80 ⁇ , from about 80 ⁇ to about 85 ⁇ , from about 85 ⁇ to about 90 ⁇ , from about 90 ⁇ to about 95 ⁇ , or from about 95 ⁇ to about 100 ⁇ , or greater than 100 ⁇ , within a time
  • a "sustained" blood and/or tissue concentration of an active agent refers to a concentration that is at least about 25%, at least about 30%, at least about 40%, or at least about 50% of the peak concentration, which concentration is maintained for a period of time of from about 1 hour to about 1.5 hours (hrs), from about 1.5 hrs to about 2 hours, from about 2 hours to about 4 hours, from about 4 hours to about 6 hours, from about 6 hours to about 8 hours, or from about 8 hours to about 12 hours, or more than 12 hours.
  • dose levels can vary as a function of the specific compound, the severity of the symptoms and the susceptibility of the subject to side effects. Preferred dosages for a given compound are readily determinable by those of skill in the art by a variety of means.
  • An active agent is administered to an individual using any available method and route suitable for drug delivery, including in vivo and ex vivo methods, as well as systemic and localized routes of administration.
  • an active agent is administered to an individual by two or more different routes of administration, which two or more different routes of administration can be carried out substantially concurrently, e.g., where an active agent is administered via a first route of administration within about 1 minute to about 48 hours of administering the active agent via a second route of administration.
  • an active agent is administered via a first route of administration within about 1 minute to about 15 minutes, within about 15 minutes to about 30 minutes, within about 30 minutes to about 1 hour, within about 1 hour to about 2 hours (hrs), within about 2 hrs to about 4 hrs, within about 4 hrs to about 8 hrs, within about 8 hrs to about 12 hrs, within about 12 hrs to about 24 hrs, or within about 24 hrs to about 48 hrs.
  • routes of administration include intranasal, intramuscular, intratracheal, intracranial, subcutaneous, intradermal, topical application, intravenous, rectal, nasal, oral and other enteral and parenteral routes of administration. Routes of administration may be combined, if desired, or adjusted depending upon the agent and/or the desired effect.
  • the composition can be administered in a single dose or in multiple doses. In some embodiments, the composition is administered orally. In other embodiments, the composition is administered
  • the composition is administered via an inhalational route. In other embodiments, the composition is administered via buccal administration. In other embodiments, the composition is administered intranasally. In other embodiments, the composition is administered intravenously. In other embodiments, the composition is administered subcutaneously. In other embodiments, the composition is administered transdermally. In other embodiments, the composition is administered intramuscularly.
  • the agent can be administered to a host using any available conventional methods and routes suitable for delivery of conventional drugs, including systemic or localized routes.
  • routes of administration contemplated by the invention include, but are not necessarily limited to, enteral, parenteral, or inhalational routes.
  • Parenteral routes of administration other than inhalation administration include, but are not necessarily limited to, topical, transdermal, subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intrasternal, and intravenous routes, i.e., any route of administration other than through the alimentary canal.
  • Parenteral administration can be carried to effect systemic or local delivery of the agent. Where systemic delivery is desired, administration can involve invasive or systemically absorbed topical or mucosal administration of pharmaceutical preparations.
  • the agent can also be delivered to the subject by enteral administration.
  • Enteral routes of administration include, but are not necessarily limited to, oral and rectal (e.g., using a suppository) delivery.
  • treatment is meant at least an amelioration of the symptoms associated with the pathological condition afflicting the host, where amelioration is used in a broad sense to refer to at least a reduction in the magnitude of a parameter, e.g. symptom, associated with the pathological condition being treated, such as a neurological disorder and pain that may be associated therewith.
  • a parameter e.g. symptom
  • treatment also includes situations where the pathological condition, or at least symptoms associated therewith, are completely inhibited, e.g. prevented from happening, or stopped, e.g. terminated, such that the host no longer suffers from the pathological condition, or at least the symptoms that characterize the pathological condition.
  • hosts are treatable according to the subject methods.
  • hosts are “mammals” or “mammalian,” where these terms are used broadly to describe organisms which are within the class mammalia, including the orders carnivore (e.g., dogs and cats), rodentia (e.g., mice, guinea pigs, and rats), non-human primates, and primates (e.g., humans, chimpanzees, and monkeys).
  • the hosts will be humans.
  • the present disclosure provides a method of treating a patient suffering from a disorder characterized by excessive NO production and/or elevated DDAH activity, the method comprising administering to said patient an effective amount of a compound of one of Formulae I-X.
  • DDAH is reversibly inhibited.
  • Disorders characterized by, or resulting from, excessive NO production and/or elevated DDAH activity include, e.g., fibrosis; sepsis; migraine headache, inflammation, autoimmune diseases, certain cancers, and lung diseases.
  • DDAH can be elevated in lung diseases.
  • the present disclosure provides methods of reducing DDAH activity in an individual, thereby treating a disorder characterized by, or resulting from, elevated DDAH levels and/or activity.
  • lung disease includes, but is not limited to, asthma, mild persistent asthma, moderate persistent asthma, severe persistent asthma, acute transient cough, chronic transient cough, acute persistent cough, chronic persistent cough, asthma related transient cough, asthma related persistent cough, chronic obstructive pulmonary disease (COPD), COPD related transient cough, COPD related persistent cough, pulmonary fibrosis, idiopathic pulmonary fibrosis, radiation induced fibrosis, silicosis, asbestos induced pulmonary or pleural fibrosis, acute lung injury, acute respiratory distress syndrome (ARDS), sarcoidosis, usual interstitial pneumonia (UIP), cystic fibrosis, Chronic lymphocytic leukemia (CLL)-associated fibrosis, Hamman-Rich syndrome, Caplan syndrome, coal worker
  • Excessive NO production refers to NO production such that NO is present at a level that is greater than (e.g., 10% greater, 20% greater, 50% greater, or more than 50% greater) a normal control level of NO.
  • elevated DDAH activity is DDAH activity that is greater than (e.g., 10% greater, 20% greater, 50% greater, or more than 50% greater) a normal control level of DDAH activity.
  • a subject method of treating a disorder characterized by excessive NO production and/or elevated DDAH activity comprises administering to an individual having a disorder characterized by excessive NO production and/or elevated DDAH activity an effective amount of a compound of one of Formulas I-X via any suitable route of administration, e.g., oral, intravenous, inhalational, subcutaneous, buccal, intranasal, subcutaneous, transdermal, etc.
  • a subject method of treating a disorder characterized by excessive NO production and/or elevated DDAH activity comprises administering to an individual having a disorder characterized by excessive NO production and/or elevated DDAH activity an effective amount of a compound of one of Formulas I-X via oral administration.
  • a subject method of treating a disorder characterized by excessive NO production and/or elevated DDAH activity comprises administering to an individual having a disorder characterized by excessive NO production and/or elevated DDAH activity an effective amount of a compound of one of Formulas I-X via an inhalational route of administration.
  • a subject method of treating a disorder characterized by excessive NO production and/or elevated DDAH activity comprises administering to an individual having a disorder characterized by excessive NO production and/or elevated DDAH activity an effective amount of a compound of one of Formulas I-X via intravenous administration.
  • a subject method of treating a disorder characterized by excessive NO production and/or elevated DDAH activity comprises administering to an individual having a disorder characterized by excessive NO production and/or elevated DDAH activity an effective amount of a compound of one of Formulas I-X via both oral administration and an inhalational route of administration.
  • an amount of a compound of one of Formulas I-X is administered via oral administration and via an inhalational route of administration substantially concurrently.
  • a subject method of treating a disorder characterized by excessive NO production and/or elevated DDAH activity comprises administering to an individual having a disorder characterized by excessive NO production and/or elevated DDAH activity an effective amount of a compound of one of Formulas I-X via both oral administration and intravenous adminsitration.
  • an amount of a compound of one of Formulas I-X is administered via oral administration and via intravenous administration substantially concurrently.
  • the present disclosure provides methods of treating fibrosis, e.g., fibrosis affecting any tissue including, for example, fibrosis of an internal organ, a cutaneous or dermal fibrotic disorder, fibrotic conditions of the eye, and vascular fibrosis.
  • Fibrosis of internal organs occurs in disorders such as pulmonary fibrosis, idiopathic fibrosis, autoimmune fibrosis, myelofibrosis, liver fibrosis, liver cirrhosis, veno-occlusive disease, mesangial proliferative glomerulonephritis, crescentic glomerulonephritis, diabetic nephropathy, renal interstitial fibrosis, renal fibrosis in subjects receiving cyclosporin, endomyocardial fibrosis, bronchiolitis obliterans (a fibrotic process that can occur after lung transplantation, after exposure to a toxin, or after an infection), and the like.
  • disorders such as pulmonary fibrosis, idiopathic fibrosis, autoimmune fibrosis, myelofibrosis, liver fibrosis, liver cirrhosis, veno-occlusive disease, mesangial proliferative glomerulonep
  • Liver fibrosis can occur in the context of a chronic hepatitis infection, or in the context of an injury (e.g., exposure, such as chronic exposure, to a toxin).
  • Dermal fibrotic disorders include, for example, scleroderma, morphea, keloids, hypertrophic scars, familial cutaneous collagenoma, and connective tissue nevi of the collagen type.
  • Fibrotic conditions of the eye include conditions such as diabetic retinopathy, post-surgical scarring (for example, after glaucoma filtering surgery, or after strabismus surgery), and proliferative vitreoretinopathy.
  • Fibrosis can be triggered by interventional therapy, where such fibrosis includes, e.g. restenosis (e.g., restenosis following balloon angioplasty or following atherectomy).
  • vascular fibrosis includes, e.g., atherosclerosis, peripheral arterial disease, and the like.
  • an effective amount of a compound of one of one of Formulae I-X is an amount that reduces collagen production by a fibroblast.
  • an effective amount of a compound of one of one of Formulae I-X is an amount that reduces collagen production by a fibroblast by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or more than 50%, compared to the amount of collagen produced by the fibroblast in the absence of the compound.
  • Liver fibrosis is an amount that reduces collagen production by a fibroblast.
  • a subject method can be used to treat liver fibrosis.
  • an effective amount of a compound of one of one of Formulae I-X is an amount that, when administered as monotherapy or combination therapy to an individual having liver fibrosis, is effective to increase liver function, or stabilize liver function.
  • liver function refers to a normal function of the liver, including, but not limited to, a synthetic function, including, but not limited to, synthesis of proteins such as serum proteins (e.g., albumin, clotting factors, alkaline phosphatase, aminotransferases (e.g., alanine transaminase, aspartate transaminase), 5'-nucleosidase, ⁇ -glutaminyltranspeptidase, etc.), synthesis of bilirubin, synthesis of cholesterol, and synthesis of bile acids; a liver metabolic function, including, but not limited to, carbohydrate metabolism, amino acid and ammonia metabolism, hormone metabolism, and lipid metabolism; detoxification of exogenous drugs; a hemodynamic function, including splanchnic and portal hemodynamics; and the like.
  • proteins such as serum proteins (e.g., albumin, clotting factors, alkaline phosphatase, aminotransferases (e.g., a
  • an effective amount of a compound of one of one of Formulae I-X is an amount that, when administered as monotherapy or combination therapy to an individual having liver fibrosis, is effective to increase an index of liver function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the index of liver function in an untreated individual, or to a placebo-treated individual.
  • Those skilled in the art can readily measure such indices of liver function, using standard assay methods, many of which are commercially available, and are used routinely in clinical settings.
  • Serum markers of liver fibrosis can also be measured as an indication of the efficacy of a subject treatment method.
  • Serum markers of liver fibrosis include, but are not limited to, hyaluronate, N-terminal procollagen III peptide, 7S domain of type IV collagen, C-terminal procollagen I peptide, and laminin.
  • Additional biochemical markers of liver fibrosis include a2-macroglobulin, haptoglobin, gamma globulin, apolipoprotein A, and gamma glutamyl transpeptidase.
  • an effective amount of a compound of one of one of Formulae I-X is an amount that, when administered as monotherapy or combination therapy to an individual having liver fibrosis, is effective to reduce a serum level of a marker of liver fibrosis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the level of the marker in an untreated individual, or to a placebo-treated individual.
  • Methods of measuring serum markers include immunological-based methods, e.g., enzyme -linked immunosorbent assays (ELISA), radioimmunoassays, and the like, using antibody specific for a given serum marker.
  • liver fibrosis reduction can be determined by analyzing a liver biopsy sample.
  • An analysis of a liver biopsy comprises assessments of two major components: necroinflammation assessed by "grade” as a measure of the severity and ongoing disease activity, and the lesions of fibrosis and parenchymal or vascular remodeling as assessed by "stage” as being reflective of long-term disease progression. See, e.g., Brunt (2000) Hepatol. 31:241-246; and METAVIR (1994) Hepatology 20: 15-20.
  • a score is assigned.
  • the METAVIR scoring system is based on an analysis of various features of a liver biopsy, including fibrosis (portal fibrosis, centrilobular fibrosis, and cirrhosis); necrosis (piecemeal and lobular necrosis, acidophilic retraction, and ballooning degeneration); inflammation (portal tract inflammation, portal lymphoid aggregates, and distribution of portal inflammation); bile duct changes; and the Knodell index (scores of periportal necrosis, lobular necrosis, portal inflammation, fibrosis, and overall disease activity).
  • each stage in the METAVIR system is as follows: score: 0, no fibrosis; score: 1, stellate enlargement of portal tract but without septa formation; score: 2, enlargement of portal tract with rare septa formation; score: 3, numerous septa without cirrhosis; and score: 4, cirrhosis.
  • Knodell's scoring system also called the Hepatitis Activity Index, classifies specimens based on scores in four categories of histologic features: I. Periportal and/or bridging necrosis; II.
  • the Ishak scoring system is described in Ishak (1995) J. Hepatol. 22:696-699. Stage 0, No fibrosis; Stage 1, Fibrous expansion of some portal areas, with or without short fibrous septa; stage 2, Fibrous expansion of most portal areas, with or without short fibrous septa; stage 3, Fibrous expansion of most portal areas with occasional portal to portal (P— P) bridging; stage 4, Fibrous expansion of portal areas with marked bridging (P— P) as well as portal-central (P— C); stage 5, Marked bridging (P— P and/or P— C) with occasional nodules (incomplete cirrhosis); stage 6, Cirrhosis, probable or definite.
  • the benefit of anti-fibrotic therapy can also be measured and assessed by using the Child- Pugh scoring system which comprises a multicomponent point system based upon abnormalities in serum bilirubin level, serum albumin level, prothrombin time, the presence and severity of ascites, and the presence and severity of encephalopathy. Based upon the presence and severity of abnormality of these parameters, patients may be placed in one of three categories of increasing severity of clinical disease: A, B, or C.
  • an effective amount of a compound of one of one of Formulae I-X is an amount that, in monotherapy or combination therapy, when administered to an individual having liver fibrosis, effects a change of one unit or more in the fibrosis stage based on pre- and post-therapy liver biopsies.
  • liver fibrosis is reduced by at least one unit in the METAVIR, the Knodell, the Scheuer, the Ludwig, or the Ishak scoring system.
  • Secondary, or indirect, indices of liver function can also be used to evaluate the efficacy of treatment with. Morphometric computerized semi-automated assessment of the quantitative degree of liver fibrosis based upon specific staining of collagen and/or serum markers of liver fibrosis can also be measured as an indication of the efficacy of a subject treatment method. Secondary indices of liver function include, but are not limited to, serum transaminase levels, prothrombin time, bilirubin, platelet count, portal pressure, albumin level, and assessment of the Child-Pugh score.
  • Pulmonary fibrosis can be caused by, e.g., chronic inflammatory processes such as sarcoidosis, Wegener's granulomatosis, etc.; infections; environmental agents (e.g., asbestos, silica, exposure to certain gases); exposure to ionizing radiation (such as radiation therapy to treat a tumor in the chest); chronic conditions (e.g., systemic lupus erythematosus; rheumatoid arthritis; etc.); and certain medications.
  • Pulmonary fibrosis can be caused by, or exacerbated by, the use of tobacco. In some patients, the cause of the pulmonary fibrosis is not understood; where the cause of pulmonary fibrosis is not understood, the pulmonary fibrosis is referred to as "idiopathic pulmonary fibrosis" (IPF).
  • IPF idiopathic pulmonary fibrosis
  • an effective amount of a compound of one of one of Formulae I-X is an amount that, in monotherapy or combination therapy, when administered to an individual having pulmonary fibrosis, is effective to reduce the pulmonary fibrosis or reduce the rate of progression of the pulmonary fibrosis by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%, or more, compared with the degree of pulmonary fibrosis in the individual prior to treatment or compared to the rate of progression of pulmonary fibrosis that would have been experienced by the patient in the absence of the monotherapy or combination therapy.
  • an effective amount of a compound of one of Formulas I-X is an amount that, in monotherapy or combination therapy, when administered to an individual having pulmonary fibrosis, is effective to increase the function of, or to reduce the rate of deterioration of, a lung of the individual by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%, or more, compared to the basal level of lung function in the individual prior to the monotherapy or combination therapy or compared to the rate of deterioration in lung function that would have been experienced by the individual in the absence of the monotherapy or combination therapy.
  • the severity of the disease, and its response to treatment, may be assessed by pulmonary function testing, e.g., spirometry, to assess lung volumes, compliance, and gas diffusion; by imaging methods, such as computerized tomography, to assess lung volumes and fibrosis; by functional testing such as treadmill exercise testing; by survival free of hospitalization; or by extension of life.
  • pulmonary function testing e.g., spirometry
  • imaging methods such as computerized tomography
  • functional testing such as treadmill exercise testing
  • survival free of hospitalization or by extension of life.
  • the present disclosure provides a method of treating radiation-induced fibrosis in an individual, the method comprising administering to the individual an effective amount of a DDAH inhibitor, e.g., where the DDAHi is a compound of any one of Formulas I-X.
  • the DDAHi inhibitor can be administered via any route of administration.
  • DDAHi is administered by a route selected from one or more of oral, inhalational, intravenous, subcutaneous, intranasal, buccal, intramuscular, and transdermal.
  • the DDAHi is administered via an oral route of administration, and the DDAHi is administered in an amount that provides for a concentration in blood of the DDAHi, within 24 hours to 48 hours of administration of the DDAHi, that is from about 10 ⁇ to 100 ⁇ .
  • the DDAHi is administered via an inhalational route of administration, and the DDAHi is administered in an amount that provides for a concentration in lung tissue of the DDAHi, within 24 hours to 48 hours of administration of the DDAHi, that is from about 10 ⁇ to 100 ⁇ .
  • the present disclosure provides a method of treating acute or chronic cough in an individual, the method comprising administering to the individual an effective amount of a DDAHi, e.g., where the DDAHi is a compound of any one of Formulas I-X.
  • the present disclosure provides methods of treating transient or persistent cough as a result of an underlying respiratory disease in an individual, the method comprising administering to the individual an effective amount of a DDAHi, e.g., where the DDAHi is a compound of any one of Formulas I-X.
  • Cough can be caused by, e.g., episodes of airway inflammation as a result of exacerbations due to acid reflux and/or microbial infection in a number of pulmonary diseases including, but not limited to, COPD, IPF, and asthma.
  • the present invention disclosure provides methods of treating idiopathic pulmonary fibrosis (IPF).
  • the methods generally involve administering to an individual in need thereof a compound of one of Formulas I-X.
  • a diagnosis of IPF is confirmed by the finding of usual interstitial pneumonia (UIP) on histopathological evaluation of lung tissue obtained by surgical biopsy.
  • UIP interstitial pneumonia
  • a diagnosis of IPF is a definite or probable IPF made by high resolution computer tomography (HRCT).
  • HRCT high resolution computer tomography
  • the presence of the following characteristics is noted: (1) presence of reticular abnormality and/or traction bronchiectasis with basal and peripheral predominance; (2) presence of honeycombing with basal and peripheral predominance; and (3) absence of atypical features such as micronodules, peribronchovascular nodules, consolidation, isolated (non-honeycomb) cysts, ground glass attenuation (or, if present, is less extensive than reticular opacity), and mediastinal adenopathy (or, if present, is not extensive enough to be visible on chest x- ray).
  • a diagnosis of definite IPF is made if characteristics (1), (2), and (3) are met.
  • a diagnosis of probable IPF is made if characteristics (1) and (3) are met.
  • an effective amount of a compound of one of Formulas I-X is an amount that, in monotherapy or combination therapy, when administered to an individual having pulmonary fibrosis, is effective to decrease IPF disease progression by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, or more, compared with a placebo control or an untreated control.
  • Disease progression is the occurrence of one or more of the following: (1) a decrease in predicted forced vital capacity (FVC) of 10% or more; (2) an increase in A-a gradient of 5 mm Hg or more; (3) a decrease of 15% or more in single breath diffusing capacity (DL C o)- Whether disease progression has occurred is determined by measuring one or more of these parameters on two consecutive occasions 4 to 14 weeks apart, and comparing the value to baseline.
  • FVC predicted forced vital capacity
  • DL C o single breath diffusing capacity
  • an individual administered with an effective amount of a compound of one of Formulas I-X exhibits a decrease in FVC of 45%, about 42%, about 40%, about 37%, about 35%, about 32%, about 30%, or less, over the same time period.
  • an effective amount of a compound of one of Formulas I-X is an amount that, in monotherapy or combination therapy, when administered to an individual having pulmonary fibrosis, is effective to increase progression-free survival time, e.g., the time from baseline (e.g., a time point from 1 day to 28 days before beginning of treatment) to death or disease progression is increased by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more, compared a placebo-treated or an untreated control individual.
  • progression-free survival time e.g., the time from baseline (e.g., a time point from 1 day to 28 days before beginning of treatment) to death or disease progression is increased by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least
  • effective amounts are any dosages that is effective to increase the progression-free survival time by at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 8 months, at least about 10 months, at least about 12 months, at least about 18 months, at least about 2 years, at least about 3 years, or longer, compared to a placebo-treated or untreated control.
  • an effective amount of a compound of one of Formulas I-X is an amount that, in monotherapy or combination therapy, when administered to an individual having pulmonary fibrosis, is effective to increase at least one parameter of lung function, e.g., an effective amount of a compound of any one of Formulas I-X is any dosage that increases at least one parameter of lung function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more, compared to an untreated individual or a placebo-treated control individual.
  • a determination of whether a parameter of lung function is increased is made by comparing the baseline value with the value at any time point after the beginning of treatment, e.g., 48 weeks after the beginning of treatment, or between two time points, e.g., about 4 to about 14 weeks apart, after the beginning of treatment.
  • an effective amount of a compound of one of Formulas I-X is an amount that, in monotherapy or combination therapy, when administered to an individual having pulmonary fibrosis, is effective to increase the FVC by at least about 10% at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4- fold, at least about 5-fold, or more compared to baseline on two consecutive occasions 4 to 14 weeks apart.
  • an effective amount of a compound of one of Formulas I-X is an amount that, in monotherapy or combination therapy, when administered to an individual having pulmonary fibrosis, results in a decrease in alveolanarterial (A-a) gradient of at least about 2 mm. Hg, at least about 7 mm Hg, at least about 10 mm Hg, at least about 12 mm Hg, at least about 15 mm Hg, or more, compared to baseline.
  • A-a alveolanarterial
  • an effective amount of a compound of one of Formulas I-X is an amount that, in monotherapy or combination therapy, when administered to an individual having pulmonary fibrosis, increases the single breath DL co by at least about 15%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or more, compared to baseline.
  • DL co is the lung diffusing capacity for carbon monoxide, and is expressed as mL CO/mm Hg/second.
  • Parameters of lung function include, but are not limited to, forced vital capacity (FVC); forced expiratory volume (FEVi); total lung capacity; partial pressure of arterial oxygen at rest; partial pressure of arterial oxygen at maximal exertion.
  • Lung function can be measured using any known method, including, but not limited to, spirometry.
  • a subject treatment method provides for treatment of an individual, regardless of what other conditions/disorders the individual may have.
  • a subject treatment method provides for treatment of an individual, regardless whether the individual has gastroesophageal reflux disease (GERD).
  • GEF gastroesophageal reflux disease
  • an individual suitable for treatment according to a subject treatment method has IPF, and has not been diagnosed as having any disease, condition, or disorder other than IPF.
  • an individual suitable for treatment according to a subject treatment method has IPF, and does not have GERD, e.g., has not been diagnosed as having GERD.
  • an individual suitable for treatment according to a subject treatment method has IPF, and also has GERD, e.g., has been diagnosed as having GERD.
  • the present invention disclosure provides methods of treating chronic obstructive pulmonary disease (COPD) and/or treating acute exacerbation of COPD.
  • COPD chronic obstructive pulmonary disease
  • the methods generally involve administering to an individual in need thereof (e.g., an individual having COPD) a compound of one of Formulas I-X.
  • Inducible NO synthase is elevated in patients with COPD.
  • a DDAHi e.g., a PPI
  • a DDAHi can reduce the levels of nitric oxide in human lung epithelial cells.
  • a DDAHi e.g., a PPI
  • a compound of one of Formulas I-X can be used to treat COPD, and to treat acute exacerbations of COPD.
  • a compound of one of Formulas I-X can be used to reduce the likelihood that an individual will develop COPD, e.g., where the individual is at increased risk of developing COPD, relative to the general population.
  • Individuals at increased risk of developing COPD include individuals who smoke tobacco- containing products (e.g., cigarettes, cigars, pipes).
  • COPD chronic obstructive pulmonary disesase
  • COPD chronic obstructive pulmonary disesase
  • COPD chronic obstructive pulmonary disesase
  • COPD chronic obstructive pulmonary disease
  • chronic obstructive pulmonary disease includes, but is not limited to, chronic bronchitis, emphysema, and/or pulmonary hypertension.
  • the present disclosure provides methods for treating sepsis.
  • the methods generally involve administering to an individual in need thereof an effective amount of a compound of one of Formulas I- X.
  • an effective amount of a compound of one of Formulas I-X is an amount that is effective to reduce an adverse symptom of sepsis.
  • an effective amount of a compound of one of Formulas I-X is an amount that is effective to reduce the use of pressor agents needed to reverse the hypotension associated with sepsis by at least about 5%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more than 80%, compared to the use of pressor agents before treatment with the compound.
  • Pressor agents include, e.g., epinephrine, isoproterenol, norepinephrine, and the like.
  • a subject method of treating sepsis comprises administering to an individual in need thereof an effective amount of a compound of one of Formulas I-X; and administering a second therapeutic agent, e.g., an antibiotic.
  • a second therapeutic agent e.g., an antibiotic
  • Individuals suitable for treatment with a subject method include individuals who have been diagnosed as having a disorder characterized by excessive NO production and/or elevated DDAH activity, where such individuals include, e.g., individuals who have been diagnosed as having a pulmonary disease, individuals who have been diagnosed as having fibrosis, individuals who have been diagnosed as having sepsis, etc. In some cases, individuals who have gastritis or gastric ulcer are specifically excluded.
  • the individual is a human.
  • the individual is a non-human mammal, e.g., a canine, a feline, a rodent (e.g., a mouse; a rat), a non-human primate, an ungulate, etc.
  • the non-human mammal is a canine, e.g., a dog that has IPF, e.g., a terrier such as a West Highland white terrier. Webb and Armstrong (2002) Can. Vet. 43:703. SCREENING METHODS
  • the present disclosure provides methods for identifying an agent that inhibits enzymatic activity of DDAH.
  • the methods generally involve contacting a DDAH polypeptide with a DDAH substrate and a test agent; and determining the effect, if any, of the test agent on DDAH activity.
  • Determining the effect of the test agent on DDAH activity involves detecting the product of action of DDAH on the DDAH substrate.
  • a test agent that reduces the amount of product produced, compared to the amount of product produced in the absence of the test agent, is considered a DDAH inhibitor.
  • Test agents that are DDAH inhibitors are candidate agents for treating a disease associated with excessive NO production and/or elevated DDAH activity.
  • a subject screening method can be used to exclude a test agent from further development when DDAH inhibition is not a desired effect.
  • determining refers to both quantitative and qualitative determinations and as such, the term “determining” is used interchangeably herein with “assaying,” “measuring,” and the like.
  • Candidate agents encompass numerous chemical classes, typically synthetic, semi-synthetic, or naturally-occurring inorganic or organic molecules. Candidate agents include those found in large libraries of synthetic or natural compounds. For example, synthetic compound libraries are commercially available from Maybridge Chemical Co. (Trevillet, Cornwall, UK),
  • Candidate agents may be small organic or inorganic compounds having a molecular weight of more than 50 and less than about 10,000 daltons, e.g., a candidate agent may have a molecular weight of from about 50 daltons to about 100 daltons, from about 100 daltons to about 150 daltons, from about 150 daltons to about 200 daltons, from about 200 daltons to about 500 daltons, from about 500 daltons to about 1000 daltons, from about 1,000 daltons to about 2500 daltons, from about 2500 daltons to about 5000 daltons, from about 5000 daltons to about 7500 daltons, or from about 7500 daltons to about 10,000 daltons.
  • Candidate agents may comprise functional groups necessary for structural interaction with proteins, particularly hydrogen bonding, and may include at least an amine, carbonyl, hydroxyl or carboxyl group, and may contain at least two of the functional chemical groups.
  • the candidate agents may comprise cyclical carbon or heterocyclic structures and/or aromatic or polyaromatic structures substituted with one or more of the above functional groups.
  • Candidate agents are also found among biomolecules including peptides, saccharides, fatty acids, steroids, purines, pyrimidines, derivatives, structural analogs or combinations thereof.
  • Assays of the invention include controls, where suitable controls include a sample (e.g., a sample comprising the DDAH polypeptide and the DDAH substrate in the absence of the test agent). Generally a plurality of assay mixtures is run in parallel with different agent concentrations to obtain a differential response to the various concentrations. Typically, one of these concentrations serves as a negative control, i.e. at zero concentration or below the level of detection.
  • a variety of other reagents may be included in the screening assay. These include reagents like salts, neutral proteins, e.g. albumin, detergents, etc., including agents that are used to facilitate optimal enzyme activity and/or reduce non-specific or background activity. Reagents that improve the efficiency of the assay, such as protease inhibitors, anti-microbial agents, etc. may be used. The components of the assay mixture are added in any order that provides for the requisite activity.
  • Incubations are performed at any suitable temperature, typically between 4°C and 40°C. Incubation periods are selected for optimum activity, but may also be optimized to facilitate rapid high-throughput screening. Typically between 0.1 hour and 1 hour will be sufficient.
  • a test compound of interest has an IC 50 of from about 1 nM to about 1 mM, e.g., from about 1 nM to about 10 nM, from about 10 nM to about 15 nM, from about 15 nM to about 25 nM, from about 25 nM to about 50 nM, from about 50 nM to about 75 nM, from about 75 nM to about 100 nM, from about 100 nM to about 150 nM, from about 150 nM to about 200 nM, from about 200 nM to about 250 nM, from about 250 nM to about 300 nM, from about 300 nM to about 350 nM, from about 350 nM to about 400 nM, from about 400 nM to about 450 nM, from about 450 nM to about 500 nM, from about 500 nM to about 750 nM, from about 750 nM to about 1 ⁇ , from about 1 nM to about 1 mM
  • Enzymatic activity of DDAH can be determined using any known assay. Colorimetric assays and fluorimetric assays can be used, depending on the nature of the product produced by action of DDAH on the DDAH substrate. The following are exemplary, non-limiting assays.
  • an assay to determine DDAH enzymatic activity is a colorimetric assay that detects product (L-citrulline) formation from the substrate ADMA.
  • DDAH can be mixed with ADMA and a test agent; and the effect of the test agent on DDAH activity is determined by measuring the amount of L-citrulline produced, using antipyrine (2,3-Dimethyl-l-phenyl-3-pyrazolin-5-one) and 2,3- butanedione oxime.
  • DDAH e.g., recombinant human DDAH1
  • ADMA antipyrine (2,3-Dimethyl-l-phenyl-3-pyrazolin-5-one
  • 2,3- butanedione oxime 2,3- butanedione oxime.
  • color developing reagent containing 2 volumes of antipyrine and 1 volume of 2,3- Butanedione oxime reagents
  • absorbance is proportional to the concentration of citrulline generated by DDAH.
  • an assay to determine DDAH enzymatic activity is a fluorimetric assay.
  • DDAH is mixed with the artificial substrate S-methyl-thiocitrulline (SMTC) and a test agent; and the effect of the test agent on DDAH activity is determined by measuring the amount of methanethiol produced.
  • DDAH metabolizes SMTC into L-citrulline and methanethiol (CH 3 -SH).
  • the thiol released from the reaction can be monitored fluorimetrically by adding 7-Diethylamino-3-(4- maleimidophenyl)-4-methylcoumarin (CPM).
  • CCM 7-Diethylamino-3-(4- maleimidophenyl)-4-methylcoumarin
  • the effect of small molecules that directly regulate DDAH activity can be monitored by comparing their fluorescence readout with that of no compound addition (control; vehicle).
  • a candidate agent can be assessed for any cytotoxic activity it may exhibit toward a living cell, using well-known assays, such as trypan blue dye exclusion, an MTT (3-(4,5-dimethylthiazol-2- yl)-2,5-diphenyl-2 H-tetrazolium bromide) assay, and the like. Agents that do not exhibit cytotoxic activity are considered candidate agents.
  • the screening method is carried out in vitro, in a cell-free assay.
  • the in vitro cell-free assay will employ a purified DDAH polypeptide, where "purified” refers to free of contaminants or any other undesired components.
  • Purified DDAH polypeptide that is suitable for a subject screening method is at least about 50% pure, at least about 60% pure, at least about 70% pure, at least about 75% pure, at least about 80% pure, at least about 85% pure, at least about 90% pure, at least about 95% pure, at least about 98% pure, at least about 99% pure, or greater than 99% pure.
  • a DDAH polypeptide suitable for use in a subject screening method can comprise an amino acid sequence having at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or 100%, amino acid sequence identity to a contiguous stretch of from about 250 amino acids to 285 amino acids of the amino acid sequence of a DDAH polypeptide as depicted in Figure 15.
  • a DDAH polypeptide is readily prepared in a variety of host cells such as unicellular microorganisms, or cells of multicellular organisms grown in in vitro culture as unicellular entities.
  • Suitable host cells include bacterial cells such as Escherichia coli; yeast cells such as Saccharomyces cerevisiae, Pichia pastoris, Hansenula polymorpha, Kluyveromyces lactis, Yarrowia lipolytica, Candida utilis, Schizosaccharomyces pombe, and the like; insect cells such as Drosophila melanogaster cells; amphibian cells such as Xenopus cells; mammalian cells, such as CHO cells, 3T3 cells, and the like.
  • the in vitro cell-free assay will employ a fusion protein, comprising a DDAH polypeptide fused in-frame to a fusion partner.
  • the fusion partner is attached to the amino terminus of the DDAH polypeptide.
  • the fusion partner is attached to the carboxyl terminus of the DDAH polypeptide.
  • the fusion partner is fused in-frame to the DDAH polypeptide at a location internal to the DDAH polypeptide.
  • Suitable fusion partners include immunological tags such as epitope tags, including, but not limited to, hemagglutinin, FLAG, and the like; proteins that provide for a detectable signal, including, but not limited to, fluorescent proteins, enzymes (e.g., ⁇ -galactosidase, luciferase, horse radish peroxidase, etc.), and the like; polypeptides that facilitate purification or isolation of the fusion protein, e.g., metal ion binding polypeptides such as 6His tags (e.g., DDAH/6His), glutathione-S-transferase, and the like; polypeptides that provide for subcellular localization; and polypeptides that provide for secretion from a cell.
  • immunological tags such as epitope tags, including, but not limited to, hemagglutinin, FLAG, and the like
  • proteins that provide for a detectable signal including, but not limited to, fluorescent proteins, enzymes (e
  • the fusion partner is an epitope tag.
  • the fusion partner is a metal chelating peptide.
  • the metal chelating peptide is a histidine multimer, e.g., (His)6.
  • a (His)6 multimer is fused to the amino terminus of a DDAH polypeptide; in other embodiments, a (His)6 multimer is fused to the carboxyl terminus of a DDAH polypeptide.
  • the (His)6-DDAH fusion protein is purified using any of a variety of available nickel affinity columns (e.g. His-bind resin, Novagen).
  • a subject screening method is carried out in vitro in a cell, e.g., a cell grown in cell culture as a unicellular entity.
  • suitable cells include, e.g., eukaryotic cells, e.g., mammalian cells such as human umbilical vein endothelial cells (HUVEC; e.g., American Type Culture Collection (ATCC) CRL-1730), human microvascular endothelial cells (HMEC-1 ; ATCC CRL-4025), PC3 cells (ATCC CRL1435), MDA-MB-231 cells (ATCC HTB26), MCF-7 cells (ATCC HTB22), HeLa cells (ATCC No.
  • HEVEC human umbilical vein endothelial cells
  • HMEC-1 human microvascular endothelial cells
  • PC3 cells ATCC CRL1435
  • MDA-MB-231 cells ATCC HTB26
  • MCF-7 cells ATCC HTB22
  • HeLa cells ATCC No.
  • CHO cells e.g., ATCC Nos. CRL9618, CCL61, CRL9096
  • 293 cells e.g., ATCC No. CRL-1573
  • Vero cells NIH 3T3 cells (e.g., ATCC No. CRL-1658), Huh-7 cells, BHK cells (e.g., ATCC No. CCL10), PC12 cells (ATCC No. CRL1721), COS cells, COS-7 cells (ATCC No. CRL1651), RATI cells, mouse L cells (ATCC No. CCLI.3), human embryonic kidney (HEK) cells (ATCC No. CRL1573), and the like.
  • a cell in vitro is contacted with a test agent; and the effect of the test agent is determined by assaying the effect of the test agent on DDAH activity in lysates made from the cells.
  • Standard abbreviations may be used, e.g., bp, base pair(s); kb, kilobase(s); pi, picoliter(s); s or sec, second(s); min, minute(s); h or hr, hour(s); aa, amino acid(s); kb, kilobase(s); bp, base pair(s); nt, nucleotide(s); i.m, intramuscular(ly); i.p., intraperitoneal(ly); s.c, subcutaneous(ly); and the like.
  • Example 1 Compounds of Formula I as Novel Class of dimethylarginine dimethylaminohydrolase (DDAH) Inhibitors
  • a high throughput screen was conducted using the Stanford High Throughput Bioscience Center (HTBC) chemical library to search for modulators of Dimethylarginine dimethylaminohydrolase (DDAH) activity.
  • HTBC Stanford High Throughput Bioscience Center
  • DDAH recombinant human DDAH1
  • ADMA recombinant human DDAH1
  • rhDDAHl recombinant human DDAH1
  • color developing reagent containing 2 volumes of Antipyrine and 1 volume of 2,3-Butanedione oxime reagents
  • absorbance is proportional to the concentration of citrulline generated by DDAH, and was measured using an AnalystGT plate reader at 485nm using a dichroic beamsplitter.
  • DDAH1 The activity of human DDAH1 was quantified using fluorimetric assay by incubating the enzyme with an artificial substrate S-methyl-thiocitrulline (SMTC).
  • DDAH metabolizes SMTC into L- citrulline and methanethiol (CH 3 -SH).
  • the thiol released from the reaction can be monitored fluorimetrically by adding 7-Diethylamino-3-(4-maleimidophenyl)-4-methylcoumarin (CPM).
  • CCM 7-Diethylamino-3-(4-maleimidophenyl)-4-methylcoumarin
  • the effect of small molecules that directly regulate DDAH activity can be monitored by comparing their fluorescence (Top Read, Ex 360-35, Em 460-40, Dichroic 425) readout with that of no compound addition (vehicle).
  • PPIs Proton Pump Inhibitors
  • esomeprazole (Nexium) was taken as a prototype to study its effect on intracellular ADMA.
  • HMEC-1 human microvascular endothelial cells
  • ATCC human microvascular endothelial cells
  • DMEM Invitrogen cat # 11995; supplemented with 10% fetal bovine serum (FBS), 4mM HEPES; GIBCO 15630 and penicillin/streptomycin.
  • FBS fetal bovine serum
  • HEPES 4mM HEPES
  • GIBCO 15630 penicillin/streptomycin
  • the cells were incubated at 37°C/5%C0 2 until -60% confluency.
  • the cells were then washed with phosphate buffered saline (PBS) and plain DMEM (DMEM with no addition of serum or the other supplements) was mixed with esomeprazole (20 ⁇ final concentration from lOOmM stock) and added to the cells.
  • PBS phosphate buffered saline
  • plain DMEM DMEM with no addition of serum or the other supplements
  • LOP AC Pharmacologically Active Compounds
  • DDAH1 The activity of human DDAH1 was quantified using fluorimetric assay by incubating the enzyme with an artificial substrate S-methyl-thiocitrulline (SMTC), as described in Example 1.
  • SMTC S-methyl-thiocitrulline
  • DDAH metabolizes SMTC into L-citrulline and methanethiol (CH 3 -SH).
  • the thiol released from the reaction can be monitored fluorimetrically by adding 7-Diethylamino-3-(4-maleimidophenyl)-4-methylcoumarin (CPM).
  • CCM 7-Diethylamino-3-(4-maleimidophenyl)-4-methylcoumarin
  • the effect of small molecules that directly regulate DDAH activity can be monitored by comparing their fluorescence (Top Read, Ex 360-35, Em 460-40, Dichroic 425) readout with that of no compound addition (vehicle).
  • NCEs new chemical entities
  • Validation study was performed by obtaining fresh powder of PD 404 directly from Sigma (Cat # P2742 at >98 high performance liquid chromatography (HPLC) purity) and preparing it in a different location and independent of the tools used to initially perform the HTS screen. Stock concentration was made using DMSO that has never been stored in the HTS facility and the prepared reagent was stored in a freezer other than where the HTS screen compounds are kept.
  • PD 404 was validated for its direct effect on DDAH activity using the fluorometric assay described above.
  • the validation study has confirmed the ability of PD 404 (50 ⁇ ) to directly inhibit DDAH activity (Figure 7, data is Mean +/- SEM from triplicate experiments using CPM fluorometric assay), compared to vehicle control.
  • the compound was also cross-validated to rule out the possibility that its apparent activity is caused by non-specific reaction quenching.
  • HMEC-1 human microvascular endothelial cells
  • ATCC human microvascular endothelial cells
  • DMEM Invitrogen cat # 11995; supplemented with 10% FBS, 4mM HEPES; GIBCO 15630 and penicillin/streptomycin.
  • the cells were incubated at 37°C/5%C0 2 until -60% confluency.
  • the cells were then washed with PBS and plain DMEM (DMEM with no addition of serum or the other supplements) was mixed with PD 404 (20 ⁇ final cone from lOOmM stock) and added to the cells.
  • the chemical library of the Stanford High Throughput Bioscience Center contains over 130,000 small molecules selected from diverse sources including Sigma, ChemDiv, MicroSource, ChemBridge, the NIH clinical collection (NIH CC), National Cancer Institute (NCI), natural products and FDA approved drug libraries using stringent criteria to maximize diversity and medicinal drug-like properties (http://htbc(dot)stanford(dot)edu/).
  • the orthogonal assays, using hits derived from the HTBC were conducted using chemicals purchased from Sigma-Aldrich (St. Louis, MO) unless indicated otherwise.
  • E. coli BL21 strain Invitrogen
  • the plasmid construct pGEX-6P-l-DDAHl was used. Empty vector control, enzyme purification and cleavage reagents were from GE Healthcare (Piscataway, NJ). Clear and black 384-well plates were from E&K Scientific (Santa Clara, CA). Antibodies directed against DDAH-1 (Abeam; Cambridge, MA) and GST (GE Healthcare) were obtained from commercial purveyors.
  • Human DDAH1 was expressed in E. coli BL21 Star (DE3) strain for protein production. In parallel, cells were also transformed with empty vector. Positive clones were selected by polymerase chain reaction (PCR) and the clones harboring DDAH were subsequently inoculated into LB broth. Bacteria were grown at 37°C (225 rpm) for 36 hours and preinduction samples were removed prior to inducing the remaining culture by adding isopropyl-beta-D-thiogalactopyranoside (IPTG; 0.1 mM final concentration) at 25°C for 18 hours.
  • IPTG isopropyl-beta-D-thiogalactopyranoside
  • the cells were harvested by centrifugation and the supernatant was discarded prior to lysing them with cell disruption buffer (containing 20mM Tris-HCl; pH 8.0; 150 mM NaCl; 2 mM ⁇ -mercaptoethanol; 1 mM phenylmethylsulfonyl fluoride (PMSF); 1 mM benzamidine and lOmM DNAse 1) and with 1% triton X-100 and lysozyme to break the peptidoglycan layer.
  • the lysate was centrifuged at 20,000g for 40 min at 4°C and the supernatant was transferred into clean tubes for SDS-PAGE and Western analyses.
  • the protein was purified using Glutathione sepharose 4B column in a batch mode according to the manufacturer's recommendations.
  • the GST-tag was cleaved off the recombinant protein using Precision Protease.
  • the purified protein was eluted, SDS-PAGE analyzed, and its identity was confirmed by Western and Mass Spectroscopy.
  • the L-citrulline assay was based upon an original test-tube method developed by Prescott and Jones in 1969 (Prescott, L.M. & Jones, M.E. Modified methods for the determination of carbamyl aspartate. Anal Biochem 32, 408-419 (1969)), which was adapted and optimized for a microplate format. Subsequently, the activity of DDAH was quantified by detecting its conversion of ADMA to citrulline using the optimized protocol. The assay was scaled up to a 384-well format for high throughput chemical screening. High Throughput Screening of Small Molecules:
  • Inhibitors were defined as compounds that reduce absorbance by at least 30% compared to control wells.
  • the hits were validated using 8-point full dose response study (50 ⁇ to 0.39 ⁇ in serial dilutions). A total of over 150 compounds, about 0.12% of the total compounds, caused a reduction in absorbance of at least 30%.
  • a modification of a validated secondary fluorometric assay was used, as described below.
  • compounds were also cross-validated by adding them in reaction mix containing all the components described above with the exception of the enzyme to rule out the possibility that their apparent activity is caused by non-specific reaction quenching and not directly inhibiting DDAH. Secondary Assay to Validate Potential DDAH inhibitors:
  • DDAH metabolizes SMTC into L-citrulline and methanethiol (CH 3 -SH).
  • DDAH (30 nM final concentration) was mixed with SMTC (100 ⁇ final concentration), CPM (50 ⁇ final concentration) and screening buffer (containing a final concentration of 0.01% Triton-X100 and lmM EDTA). The reaction mix was added to black 384-well plates to validate primary hits that modulate DDAH activity.
  • CH 3 -SH The release of CH 3 -SH was monitored fluorimetrically by adding 7-Diethylamino-3-(4- maleimidophenyl)-4-methylcoumarin (CPM) as described in Linsky (Linsky, T. & Fast, W. A continuous, fluorescent, high-throughput assay for human dimethylarginine dimethylaminohydrolase-1. J Biomol Screen 16, 1089-1097 (2011)).
  • CPM 7-Diethylamino-3-(4- maleimidophenyl)-4-methylcoumarin
  • HMVECs primary microvascular endothelial cells
  • the cells were then pelleted down by centrifugation and lysed by adding lysis buffer (containing lOOmM Na 2 HP04; 1% NP-40; IX protease and phosphatase inhibitors). The suspension was kept on ice for 30 minutes prior to centrifugation at 13,000 rpm for 30 minutes at 4°C. Finally, the cell debris was removed and the supernatant was collected for the citrulline assay.
  • the citrulline assay was performed in a microplate assay as described above by transferring equimolar amounts of cell lysate and adding 0.5 volume of color-developing reagent. The mix was incubated at 60°C for 90 minutes and absorbance was measured as described above. Known concentrations of commercial citrulline were used to construct standard curves and to estimate the concentration of citrulline in the samples.
  • a human DDAH-1 (858 bp)-encoding plasmid was successfully transformed into an E. coli system and the polymerase chain reaction (PCR) -positive clones were used for the production of rhDDAHl.
  • Western blot analysis using both anti-DDAHl and anti-glutathione-S-transferase (GST) antibodies confirmed that rhDDAHl tagged with GST (56.5kDa) was expressed only in the cells transformed with the vector encoding DDAH and induced by IPTG (Figure 10).
  • Western blot analysis shows the production of GST-DDAH (56.5kDa).
  • lanes 1,3 pre -induction
  • lane -2 post-induction sample of an empty vector
  • lane 4 isopropyl ⁇ -D-l-thiogalactopyranoside (IPTG) induction of DDAH vector.
  • Lane-M is SeeBlue Plus molecular weight marker.
  • FIG. 11 A shows SDS- PAGE analysis of purified human DDAH1.
  • PI pre -induction
  • LY lysate
  • FT flow through
  • Wl wash
  • E eluent
  • M lkb-i- marker.
  • Figure 1 IB shows Western blot showing purified (after GST cleavage) recombinant human DDAH1 (-37 kDa).
  • Figure 12 shows a citrulline assay showing that the conversion of ADMA to L-citrulline by DDAH1 is proportional to time, temperature and enzyme concentration. Data are averaged from at least duplicate experiments.
  • the biochemical properties of the assay were optimized, as described above.
  • the technique was modified so as to reduce the number of steps and facilitate robotic handling and throughput.
  • HTS was performed using 384-well plates.
  • the Stanford HTBC is equipped with a Caliper Life Sciences workstation for sample preparation and analysis, Titertek multidrops, microplate dispenser and automated liquid handler and laboratory robotics for screening of chemical libraries.
  • the Z'-score was consistently found to be between 0.7 and 0.8, indicating the robustness of the assay.
  • the feasibility of the assay was demonstrated in cell culture study by quantifying the amount of L-citrulline in endothelial cells treated with L-arginine or vehicle.
  • the validation assay also confirmed known DDAH inhibitors such as chloromercuribenzoate and ebselen and identified several new, potent inhibitors of human DDAH1.
  • Figure 14 shows curve fit data showing inhibition of human DDAH-1 activity by selected small molecules using the CPM assay: A) ChemDiv Compound 2548-0707; B) ChemDiv Compound 2548-0703; C) 4-MMP; and D) SCH-202676.
  • the inhibitory concentration at 50% (IC 50 ) was calculated using Assay Explorer software.
  • Table 1 Inhibitors of human DDAH-1. The following compounds were validated in full dose -response curves. The inhibitory concentration at 50% (IC 50 ) was calculated using Assay Explorer software.
  • DDAH Dimethylaminohydrolase
  • Lung fibroblasts from patients with late-stage IPF were isolated and extensively characterized by immunofluorescence staining for the expression of pan-mesenchymal markers such as vimentin and collagen IV; fibroblasts marker: Fibroblast Specific Protein (FSPl ; S100A4); and smooth muscle cell markers such as alpha smooth muscle actin (oc-SMA); skeletal-myosin heavy chain (sk- MHC); Caldesmon; Calponin and Desmin.
  • pan-mesenchymal markers such as vimentin and collagen IV
  • fibroblasts marker Fibroblast Specific Protein (FSPl ; S100A4)
  • smooth muscle cell markers such as alpha smooth muscle actin (oc-SMA); skeletal-myosin heavy chain (sk- MHC); Caldesmon; Calponin and Desmin.
  • endothelial phenotype was ruled out by negative staining for the endothelial cell-specific marker CD31.
  • TGF- ⁇ transforming growth factor-1
  • PPI proton pump inhibitor
  • the amount of collagen in each well was estimated from a standard curve and the collagen content in each sample was normalized to total cellular protein from the respective well and was expressed as ⁇ g collagen per milligram of protein.
  • Human Lung Carcinoma cell line with type II alveolar epithelial cell property is a cell line with type II alveolar epithelial cell property:
  • Human lung carcinoma cell line (A-549) was purchased from the American Type Culture Collection (ATCC; Manassas, VA; Cat # CCL-185). This cell line is widely used to study human alveolar epithelial (AT II) cells due to the similarities with primary AT II cells (Lieber M et al "A continuous tumor-cell line from a human lung carcinoma with properties of type II alveolar epithelial cells"; Int. J. Cancer 1976; 17(1): 62-70; PMID: 175022). A detailed description and characterization (including additional references) of this cell line are available at the ATCC web site
  • the cells were cultured in Kaighn's Modification of Ham's F-12K (Invitrogen/Gibco cat # 21127) supplemented with FBS (10%), Pen/Step (1%) and HEPES (2 mL in 500 mL Media). It was also established that the cells could as well be cultured in standard Dulbecco' s Modified Eagle Medium (DMEM; Gibco cat # 11995-065) supplemented with FBS (10%), Pen/Step (1%) and HEPES (2 mL in 500 mL Media).
  • DMEM Dulbecco' s Modified Eagle Medium
  • PPIs Protein pump inhibitors
  • DDAH inhibitors were used: Lansoprazole; Esomeprazole; and Rabeprazole.
  • a "vehicle only” sample served as a “no DDAH” control.
  • FIG. 19 Treatment with proton pump inhibitors (PPIs; 20 ⁇ ) ameliorated serum- induced lung alveolar epithelial cell proliferation.
  • PPIs proton pump inhibitors
  • Human lung epithelial cell line (A -549) cells were rendered quiescent, then serum-stimulated to induced re-entry into the cell cycle.
  • BrdU (4 h) incorporation was assessed. Data are mean ⁇ SEM (duplicates).
  • Example 7 Inhibition of DDAH by PPIs is reversible
  • FIG. 20 A dilution assay demonstrating reversible inhibition of DDAH activity by PPIs.
  • Omeprazole IC 50 ⁇ 60 ⁇
  • Example 8 Effect of a PPI (Omeprazole) on Cellular ADMA
  • Omeprazole reduced the levels of nitric oxide in the human alveolar epithelial cell line.
  • Lung fibroblasts were isolated from patients diagnosed with IPF according to International Standards. Isolated fibroblasts were seeded at 6 x 10 4 and synchronized the following day. On day-3, the cells were stimulated with serum stimulation in the absence or presence of recombinant transforming growth factor-1 (TGF- ⁇ ) in the presence of the proton pump inhibitor Omeprazole (final concentration 50 or 100 ⁇ )); L-257 (final concentration 50 ⁇ ) or TGF- ⁇ inhibitor A83-01 (final concentration 20 ⁇ ) controls; or vehicle for 24 hours.
  • TGF- ⁇ transforming growth factor-1
  • PPIs are cytotoxic to human alveolar epithelial cells (A-549) were treated with vehicle, or varying concentrations of PPI (Omeprazole) or a known DDAH inhibitor (L- 257; Leiper J et al; Nature Med 2007; 13(2): 198-203) and cytotoxicity was assessed by the release of lactate dehydrogenase (LDH) into conditioned media.
  • LDH lactate dehydrogenase
  • PPI (Omeprazole) is not cytotoxic to human alveolar epithelial cells at least up to 300 ⁇ , a concentration 3-6 fold higher than the concentration of PPIs at which anti-fibrotic, anti-proliferative, and anti-apoptotic effects were observed as described herein. Cytotoxicity was also not observed at least up to 300 ⁇ in mouse alveolar epithelial (MLE-12) cells (Figure 28). Mean +/- SEM from Duplicate Experiments. * p ⁇ 0.05.
  • GER gastroesophageal reflux
  • PPIs inhibit DDAH, which regulates metabolism of nitric oxide synthetase, in cultured IPF lung fibroblasts and block TGF- ⁇ induced collagen expression. DDAH levels and inducible nitric oxide synthetase levels are increased in IPF lung and suppression of DDAH in the murine bleomycin model attenuates lung fibrosis.
  • Example 15 Effect of DDAHi on iNOS expression in lung cells
  • Example 16 Effect of PPIs on gene expression associated with fibrosis
  • Heme Oxygenase 1 is an essential enzyme in heme catabolism that cleaves heme to form biliverdin which is subsequently converted to bilirubin and carbon monoxide (CO).
  • PPI inhibition of fibrosis may also function through the inhibition of pro-inflammatory and profibrotic genes (e.g., adhesion associated pro-inflammatory molecules, profibrotic associated adhesion molecules, profibrotic associated transcription factors, profibrotic associated transcription factor receptors, profibrotic associated proteases, etc.).
  • pro-inflammatory and profibrotic genes e.g., adhesion associated pro-inflammatory molecules, profibrotic associated adhesion molecules, profibrotic associated transcription factors, profibrotic associated transcription factor receptors, profibrotic associated proteases, etc.
  • IPF human fibroblasts were treated with PPI (5 ⁇ , 10 ⁇ , or 50 ⁇ ), vehicle, or L-257 and gene expression of inegrins (ITGA5, ITGBl, ITGB3, ITGB5, ITGB6 and ITGB8), transforming growth factor-beta (TGF-beta) family members (TGFB1, TGFBR1 and TGFBR2), bone morphogenic protein (BMP) family members (BMP2, BMP4, MBP6, BMPR1B and BMPR2), SMAD6 and matrix metalloproteinase-8 (MMP8) were all measured following treatment.
  • inegrins ITGA5, ITGBl, ITGB3, ITGB5, ITGB6 and ITGB8
  • TGF-beta transforming growth factor-beta family members
  • BMP2 bone morphogenic protein family members
  • BMP2BMP4, MBP6, BMPR1B and BMPR2 bone morphogenic protein
  • SMAD6 matrix metalloproteinase-8
  • ITGA5, ITGBl, ITGB3, ITGB5, ITGB6, ITGB8, TGFB1, TGFBR1, TGFBR2, BMP2, BMP4, MBP6, BMPR1B, BMPR2, SMAD6 and MMP8 were all found to be significantly down regulated at at least one dosage following PPI treatment as compared to vehicle control ( Figures 32-48).
  • fibroblasts and bronchial epithelial cells were collected from the lungs of patients with COPD. Cells were exposed to PPI (Esomeprazole) or vehicle for 24 hours. Following treatment gene expression was evaluated.
  • COPD fibroblasts exposed to PPI displayed a 10-fold increase in HOI gene expression as compared to vehicle controls ( Figure 49).
  • COPD bronchial epithelial cells exposed to PPI displayed a four-fold increase in HOI gene expression as compared to vehicle controls ( Figure 50).

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Abstract

La présente invention concerne des modulateurs de DDAH. Donc, la présente invention concerne un procédé de traitement d'un patient souffrant d'un trouble caractérisé par une production de NO excessive et/ou une activité de DDAH élevée, le procédé comprenant l'administration audit patient d'une quantité efficace d'un composé de l'une des formules I-X. La présente invention concerne également une composition pharmaceutique comprenant un composé de l'une des formules I-X.
PCT/US2014/032189 2013-03-29 2014-03-28 Inhibiteurs de diméthylarginine diméthylaminohydrolase et leurs procédés d'utilisation Ceased WO2014160947A1 (fr)

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017077008A1 (fr) * 2015-11-03 2017-05-11 Hochschule Darmstadt Inhibiteurs de hdac8 sélectifs et leurs utilisations
CN107921025A (zh) * 2015-03-08 2018-04-17 卡斯西部储备大学 用于治疗纤维症的短链脱氢酶活性的抑制剂
US10011611B2 (en) 2015-08-14 2018-07-03 Reaction Biology Corp. Histone deacetylase inhibitors and methods for use thereof
US10301320B2 (en) 2012-04-16 2019-05-28 University Of Kentucky Research Foundation Compositions and methods of modulating 15-PGDH activity
US10869871B2 (en) 2013-10-15 2020-12-22 Case Western Reserve University Compositions and methods of modulating short-chain dehydrogenase activity
CN112312911A (zh) * 2018-02-28 2021-02-02 贝勒医学院 质子泵抑制剂及其在化疗放疗诱发的组织炎症和瘢痕中的使用方法
US11690847B2 (en) 2016-11-30 2023-07-04 Case Western Reserve University Combinations of 15-PGDH inhibitors with corticosteroids and/or TNF inhibitors and uses thereof
US11718589B2 (en) 2017-02-06 2023-08-08 Case Western Reserve University Compositions and methods of modulating short-chain dehydrogenase
US12336982B2 (en) 2018-11-21 2025-06-24 Rodeo Therapeutics Corporation Compositions and methods of modulating short-chain dehydrogenase activity

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070060622A1 (en) * 2004-01-30 2007-03-15 Eisai Co., Ltd. Compositions and methods using proton pump inhibitors
US20090069331A1 (en) * 2004-11-12 2009-03-12 UCL Biomedica PLC c/o Finance Division University College of London Guanidine derivatives as inhibitors of ddah

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070060622A1 (en) * 2004-01-30 2007-03-15 Eisai Co., Ltd. Compositions and methods using proton pump inhibitors
US20090069331A1 (en) * 2004-11-12 2009-03-12 UCL Biomedica PLC c/o Finance Division University College of London Guanidine derivatives as inhibitors of ddah

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
LEE ET AL.: "Gastroesophageal Reflux Therapy Is Associated with Longer Survival in Patients with Idiopathic Pulmonary Fibrosis", AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, vol. 184, no. 12, 2011, pages 1390 - 1394, Retrieved from the Internet <URL:http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3262030/pdf/AJRCCM184121390.pdf> [retrieved on 20140721] *
RAGHU ET AL.: "High prevalence of abnormal acid gastro-oesophageal reflux in idiopathic pulmonary fibrosis", EUROPEAN RESPIRATORY JOURNAL, vol. 27, no. 1, 2006, pages 136 - 142, Retrieved from the Internet <URL:http://erj.ersjournals.com/content/27/1/136.full.pdf> [retrieved on 20140721] *

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US10301320B2 (en) 2012-04-16 2019-05-28 University Of Kentucky Research Foundation Compositions and methods of modulating 15-PGDH activity
US10869871B2 (en) 2013-10-15 2020-12-22 Case Western Reserve University Compositions and methods of modulating short-chain dehydrogenase activity
EP3267995A4 (fr) * 2015-03-08 2019-02-27 Case Western Reserve University Inhibiteurs de l'activité de la déshydrogénase à chaîne courte pour le traitement de la fibrose
AU2016229918B2 (en) * 2015-03-08 2020-10-29 Case Western Reserve University Inhibitors of short-chain dehydrogenase activity for treating fibrosis
CN107921025A (zh) * 2015-03-08 2018-04-17 卡斯西部储备大学 用于治疗纤维症的短链脱氢酶活性的抑制剂
US10945998B2 (en) 2015-03-08 2021-03-16 Case Western Reserve University Inhibitors of short-chain dehydrogenase activity for treating fibrosis
AU2021200610B2 (en) * 2015-03-08 2022-09-15 Case Western Reserve University Inhibitors of short-chain dehydrogenase activity for treating fibrosis
US10011611B2 (en) 2015-08-14 2018-07-03 Reaction Biology Corp. Histone deacetylase inhibitors and methods for use thereof
WO2017077008A1 (fr) * 2015-11-03 2017-05-11 Hochschule Darmstadt Inhibiteurs de hdac8 sélectifs et leurs utilisations
US11801251B2 (en) 2015-11-03 2023-10-31 Hochschule Darmstadt Selective HDAC8 inhibitors and their uses
US11690847B2 (en) 2016-11-30 2023-07-04 Case Western Reserve University Combinations of 15-PGDH inhibitors with corticosteroids and/or TNF inhibitors and uses thereof
US11718589B2 (en) 2017-02-06 2023-08-08 Case Western Reserve University Compositions and methods of modulating short-chain dehydrogenase
CN112312911A (zh) * 2018-02-28 2021-02-02 贝勒医学院 质子泵抑制剂及其在化疗放疗诱发的组织炎症和瘢痕中的使用方法
EP3758703A4 (fr) * 2018-02-28 2022-03-09 Baylor College of Medicine Inhibiteurs de pompe à protons et procédés d'utilisation dans l'inflammation tissulaire et la formation de cicatrice induites par chimioradiothérapie
US12336982B2 (en) 2018-11-21 2025-06-24 Rodeo Therapeutics Corporation Compositions and methods of modulating short-chain dehydrogenase activity

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