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WO2017011917A1 - Méthodes de traitement et de prévention de la polykystose rénale (pkd) au moyen de modulateurs et d'activateurs de la protéine kinase activée par l'amp (ampk) - Google Patents

Méthodes de traitement et de prévention de la polykystose rénale (pkd) au moyen de modulateurs et d'activateurs de la protéine kinase activée par l'amp (ampk) Download PDF

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Publication number
WO2017011917A1
WO2017011917A1 PCT/CA2016/050862 CA2016050862W WO2017011917A1 WO 2017011917 A1 WO2017011917 A1 WO 2017011917A1 CA 2016050862 W CA2016050862 W CA 2016050862W WO 2017011917 A1 WO2017011917 A1 WO 2017011917A1
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Prior art keywords
ampk
subject
pkd
modulator
kidney disease
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Gilles Dube
Roger Leger
Jerome ROSSERT
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Thrasos Therapeutics Inc Canada
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Thrasos Therapeutics Inc Canada
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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
    • A61K31/12—Ketones
    • 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
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
    • 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
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism

Definitions

  • PTD Polycystic kidney diseases
  • ADPKD autosomal dominant polycystic kidney disease
  • ARPKD autosomal recessive polycystic kidney disease
  • nephronophthisis medullary cystic kidney disease
  • multicystic renal dysplasia medullary sponge kidney
  • glomerulocystic kidney disease Bardet-Biedl syndrome, Joubert syndrome, Meckel-Gruber syndrome, and MODY-5 syndrome.
  • ADPKD is the most common form of the disease, and signs and symptoms of ADPKD typically develop in adulthood.
  • Symptoms of polycystic kidney disease include high blood pressure, kidney failure, back or side pain, headache, increase in abdomen size, blood in urine, frequent urination, kidney stones, urinary tract infections, and/or kidney infections.
  • Current treatments are limited to careful control of blood pressure, prompt treatment with antibiotics of kidney or bladder infection, pain medication, and maintenance of a healthy diet.
  • the present invention is based, at least in part, on the identification of AMPK modulator and activator compounds which are surprisingly useful for arresting cystic growth and, thus, treating polycystic kidney disease (PKD).
  • PPD polycystic kidney disease
  • the invention provides a method for treating polycystic kidney disease (PKD) in a subject, the method comprising administering a modulator of AMP- activated protein kinase (AMPK) to the subject, thereby treating the polycystic kidney disease in the subject.
  • PPD polycystic kidney disease
  • AMPK AMP-activated protein kinase
  • the invention provides a method for preventing polycystic kidney disease (PKD) in a subject, the method comprising administering a modulator of AMP -activated protein kinase (AMPK) to the subject, thereby preventing the polycystic kidney disease in the subject.
  • PPD polycystic kidney disease
  • AMPK AMP -activated protein kinase
  • the invention provides a method for preventing polycystic kidney disease (PKD) in a subject, the method comprising administering an activator of AMP-activated protein kinase (AMPK) to the subject, thereby preventing the polycystic kidney disease in the subject.
  • PPD polycystic kidney disease
  • AMPK AMP-activated protein kinase
  • the activator of AMPK is a compound listed in Table 1.
  • the modulator of AMPK is a compound listed in Table 2.
  • the modulator or the activator of AMPK is formulated with a pharmaceutically acceptable carrier. In one embodiment, the modulator or the activator of AMPK is administered to the subject orally. In another embodiment, the modulator or the activator of AMPK is administered to the subject topically, enterally, or parenterally.
  • the PKD is autosomal dominant polycystic kidney disease (ADPKD). In another embodiment, the PKD is autosomal recessive polycystic kidney disease (ARPKD). In yet another embodiment, the PKD is selected from the group consisting of nephronophthisis, medullary cystic kidney disease, multicystic renal dysplasia, medullary sponge kidney, glomerulocystic kidney disease, Bardet-Biedl syndrome, Joubert syndrome, Meckel-Gruber syndrome, and MODY-5 syndrome.
  • ADPKD autosomal dominant polycystic kidney disease
  • ARPKD autosomal recessive polycystic kidney disease
  • the PKD is selected from the group consisting of nephronophthisis, medullary cystic kidney disease, multicystic renal dysplasia, medullary sponge kidney, glomerulocystic kidney disease, Bardet-Biedl syndrome, Joubert syndrome, Meckel-Gruber syndrome
  • the modulator or the activator of AMPK is administered to the subject at a dosage of 0.0001 to 10,000 mg/kg body weight per day. In another embodiment, the modulator or the activator of AMPK is administered to the subject at a dosage of 1 to 100 mg/kg body weight per day.
  • the method further comprises selecting a subject suspected of having PKD, at risk for having PKD, or having PKD.
  • the invention provides a kit comprising a modulator of AMPK and instructions for use in treating or preventing polycystic kidney disease in a subject.
  • the invention provides a kit comprising an activator of AMPK and instructions for use in treating or preventing polycystic kidney disease in a subject.
  • the present invention is based, in part, on the discovery by the inventors of AMPK modulator and activator compounds which are surprisingly useful for arresting cystic growth and, thus, treating polycystic kidney disease (PKD).
  • PPD polycystic kidney disease
  • Ranges provided herein are understood to be shorthand for all of the values within the range.
  • a range of 1 to 50 is understood to include any number, combination of numbers, or sub-range from the group consisting 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50.
  • a "subject,” as used herein, is preferably a mammal, such as a human, but can also be an animal, e.g., domestic animals (e.g., dogs, cats and the like), farm animals (e.g., cows, sheep, pigs, horses and the like) and laboratory animals (e.g., rats, mice, guinea pigs and the like).
  • the subject is a human.
  • an "effective amount" of a compound, as used herein, is a quantity sufficient to achieve a desired therapeutic and/or prophylactic effect, for example, an amount which results in the prevention of or a decrease in the symptoms associated with a disease that is being treated, e.g., a kidney disease or disorder.
  • the amount of compound administered to the subject will depend on the type and severity of the disease and on the characteristics of the individual, such as general health, age, sex, body weight and tolerance to drugs. 1 1 will also depend on the degree, severity and type of disease. The skilled artisan will be able to determine appropriate dosages depending on these and other factors.
  • an effective amount of the compounds of the present invention sufficient for achieving a therapeutic or prophylactic effect, range from about 0.000001 mg per kilogram body weight per day, to about 10,000 mg per kilogram body weight per day.
  • the dosage ranges are from about 0.0001 mg per kilogram body weight per day to about 100 mg per kilogram body weight per day.
  • the compounds of the present invention can also be administered in combination with each other, or with one or more additional therapeutic compounds.
  • the term “local” or “locally,” as in local administration or coadministration of one or more therapeutics, refers to the delivery of a compound to a bodily site that is proximate or nearby the site of disease or injury, adjacent or immediately nearby the site of disease or injury, at the perimeter of or in contact with disease site or injury site, or within or inside the diseased or injured tissue or organ. Local administration generally excludes systemic administration routes.
  • the term "regimen” refers to the various parameters that characterize how a drug or agent is administered, including the dosage level, timing, and iterations, as well as the ratio of different drugs or agents to one another.
  • the term “regimen” refers to the various parameters that characterize how a drug or agent is administered, including the dosage level, timing, and iterations, as well as the ratio of different drugs or agents to one another.
  • “iterations” refer to the general concept of repeating sets of administering one or more agents. For example, a combination of drug X and drug Y may be given (co-administered at or about at the same time and in any order) to a patient on a first day at dose Z. Drugs X and Y may then be administered (co-administered at or about at the same time and in any order) again at dose Z, or another dose, on a second day.
  • the timing between the first and second days can be 1 day or anywhere up to several days, or a week, or several weeks, or months.
  • the iterative administrations may also occur on the same day, separated by a specified number of minutes (e.g., 10 minutes, 20 minutes, 30 minutes or more) or hours (e.g., 1 hour, 2 hours, 4 hours, 6 hours, 12 hours).
  • An effective dosing regimen may be determinable by those of ordinary skill in the art, e.g., prescribing physician, using standard practices.
  • the term "pharmaceutically effective regimen” refers to a systematic plan for the administration of one or more therapeutic compounds which includes aspects such as drug concentrations, amounts or levels, timing, and repetition, and any changes therein made during the course of the drug administration, which when administered is effective in treating a kidney disease or disorder.
  • PKD kidney disease
  • co-administering refers to the act of administering two or more agents, therapeutics, compounds, therapies, or the like, at or about the same time.
  • the order or sequence of administering the different agents of the invention may vary and is not confined to any particular sequence.
  • Coadministering may also refer to the situation where two or more agents are administered to different regions of the body or via different delivery schemes, e.g., where a first agent is administered systemically and a second agent is administered locally at the site of tissue injury, or where a first agent is administered locally and a second agent is administering systemically into the blood.
  • pharmaceutically acceptable refers to a material, (e.g., a carrier or diluent), which does not abrogate the biological activity or properties of the compounds described herein, and is relatively nontoxic (i.e., the material is administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained).
  • the term "selectively" means tending to occur at a higher frequency in one population than in another population.
  • 5' adenosine monophosphate (AMP)-activated protein kinase (AMPK) plays a key role as a regulator of cellular energy homeostatis and exists as a heterotrimeric complex composed of a catalytic alpha subunit and regulatory beta and gamma subunits. Binding of 5' adenosine monophosphate (AMP) to the gamma subunit activates AMPK, which then positively regulates several signaling pathways, including fatty acid oxidation and autophagy, and negatively regulates several signaling pathways, including gluconeogenesis, lipid synthesis, and protein synthesis.
  • AMP 5' adenosine monophosphate
  • AMPK 5' adenosine monophosphate
  • the invention provides AMPK modulators and activators which can surprisingly be used to treat polycystic kidney diseases.
  • AMPK activator refers to a compound which is capable of increasing the activity of 5' adenosine monophosphate (AMP)-activated protein kinase (AMPK). In one embodiment, the AMPK activator is a small molecule.
  • AMPK modulator refers to a compound which is capable of modulating the activity of 5' adenosine monophosphate (AMP)-activated protein kinase (AMPK). In one embodiment, the AMPK modulator is a small molecule.
  • the small molecule AMPK modulators and activators of the instant invention are characterized by particular functional features or properties.
  • the small molecules may directly activate AMPK or indirectly activate AMPK.
  • the small molecules may directly modulator AMPK or indirectly modulate AMPK.
  • the terms "small molecule compound”, “small molecule drug” , “small molecule”, “small molecule activator,” and “small molecule modulator” are used interchangeably herein to refer to the compounds of the present invention screened for an effect on AMPK and their ability to modulator and/or activate AMPK in order to treat polycystic kidney disease.
  • analogue or “functional analogue” refers to a chemical compound or small molecule that is structurally similar to a parent compound, but differs slightly in composition (e.g., one or more atoms or functional groups are added, removed, or modified).
  • An analogue may or may not have different chemical or physical properties than the original compound and may or may not have improved biological and/or chemical activity.
  • the analogue may be more hydrophobic or it may have altered activity (increased, decreased, or identical to parent compound) as compared to the parent compound.
  • the analogue may be a naturally or non-naturally occurring (e.g. , recombinant) variant of the original compound.
  • analogues include isomers (enantiomers, diasteromers, and the like) and other types of chiral variants of a compound, as well as structural isomers.
  • the analogue may be a branched or cyclic variant of a linear compound.
  • a linear compound may have an analogue that is branched or otherwise substituted to impart certain desirable properties (e.g. , improve hydrophilicity or bioavailability).
  • derivative refers to a chemically or biologically modified version of a chemical compound or small molecule that is structurally similar to a parent compound and (actually or theoretically) derivable from that parent compound.
  • “derivative” differs from an “analogue” or “functional analogue” in that a parent compound may be the starting material to generate a "derivative,” whereas the parent compound may not necessarily be used as the starting material to generate an "analogue” or “functional analogue.”
  • a derivative may or may not have different chemical or physical properties of the parent compound. For example, the derivative may be more hydrophilic or it may have altered reactivity as compared to the parent compound.
  • Derivatization i.e. , modification by chemical or other means
  • a hydrogen may be substituted with a halogen, such as fluorine or chlorine, or a hydroxyl group (--OH) may be replaced with a carboxylic acid moiety (--COOH).
  • derivative also includes conjugates, and prodrugs of a parent compound (i.e. , chemically modified derivatives which can be converted into the original compound under physiological conditions).
  • the prodrug may be an inactive form of an active agent. Under physiological conditions, the prodrug may be converted into the active form of the compound.
  • Prodrugs may be formed, for example, by replacing one or two hydrogen atoms on nitrogen atoms by an acyl group (acyl prodrugs) or a carbamate group (carbamate prodrugs).
  • prodrugs More detailed information relating to prodrugs is found, for example, in Fleisher et al. , Advanced Drug Delivery Reviews 19 (1996) 115; Design of Prodrugs, H. Bundgaard (ed.), Elsevier, 1985; and H. Bundgaard, Drugs of the Future 16 (1991) 443.
  • derivative is also used to describe all solvates, for example hydrates or adducts (e.g. , adducts with alcohols), active metabolites, and salts of the parent compound.
  • the type of salt that may be prepared depends on the nature of the moieties within the compound.
  • acidic groups such as carboxylic acid groups can form alkali metal salts or alkaline earth metal salts (e.g., sodium salts, potassium salts, magnesium salts, calcium salts, and salts with physiologically tolerable quaternary ammonium ions and acid addition salts with ammonia and physiologically tolerable organic amines such as triethylamine, ethanolamine, or tris-(2-hydroxyethyl)amine).
  • alkali metal salts or alkaline earth metal salts e.g., sodium salts, potassium salts, magnesium salts, calcium salts, and salts with physiologically tolerable quaternary ammonium ions and acid addition salts with ammonia and physiologically tolerable organic amines such as triethylamine, ethanolamine, or tris-(2-hydroxyethyl)amine.
  • Basic groups can form acid addition salts, for example with inorganic acids such as hydrochloric acid (“HQ"), sulfuric acid, or phosphoric acid, or with organic carboxylic acids and sulfonic acids such as acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, methanesulfonic acid, or p-toluenesulfonic acid.
  • Compounds which simultaneously contain a basic group and an acidic group such as a carboxyl group in addition to basic nitrogen atoms can be present as zwitterions. Salts can be obtained by customary methods known to those skilled in the art, for example by combining a compound with an inorganic or organic acid or base in a solvent or diluent, or from other salts by cation exchange or anion exchange.
  • the small molecule AMPK modulators and activators of the present invention are selected or designed to bind directly to AMPK in order to modulate and/or activate AMPK, or are selected or designed to indirectly modulate and/or activate AMPK, e.g., by modulating an upstream molecular target which, in turn, activates AMPK.
  • AMPK small molecule activator compounds are described, for example, in Table 1 , below.
  • AMPK small molecule modulator compounds are described, for example, in Table 2, below.
  • AMPK modulators and activators of the invention may be made or selected by several methods known in the art. Screening procedures can be used to identify small molecules from libraries which activate AMPK or bind AMPK.
  • Screening procedures can be used to identify small molecules from libraries which activate AMPK or bind AMPK.
  • One method, Chemetics® (Nuevolutions) uses DNA tags for each molecule in the library to facilitate selection.
  • the Chemetics® system allows screening of millions of compounds for target binding.
  • Patents related to small molecule libraries and tag based screening are U.S. Pat. Application Nos. 20070026397; 20060292603; 20060269920; 20060246450;
  • tags can be amplified, using for example, polymerase chain reaction, to produce many copies of the tag and identify the tag by sequencing. The sequence of the tag then identifies the structure of the binding molecule, which can be synthesized in pure form and tested for AMPK activity.
  • combinatorial chemical libraries which may be used to identify moieties of the invention include, but are not limited to, peptide libraries (see, e.g., U.S. Pat. No. 5,010,175, Furka, / «/. J. Pept. Prot. Res. 37:487 493 (1991) and Houghton et al., Nature 354:84 88 (1991)).
  • Other chemistries for generating chemical diversity libraries are well known in the art and can be used. Such chemistries include, but are not limited to: peptoids (e.g., PCT Publication No.
  • nucleic acid libraries see Ausubel, Berger and Russell & Sambrook, all supra
  • peptide nucleic acid libraries see, e.g., U.S. Pat. No. 5,539,083
  • carbohydrate libraries see, e.g., Liang et al., Science, 274: 1520 1522 (1996) and U.S. Pat. No. 5,593,853
  • small organic molecule libraries see, e.g., benzodiazepines, Baum C&EN, Jan 18, page 33 (1993);
  • small molecules of the invention may be selected using virtual screening methods.
  • Virtual screening technologies predict which small molecules from a library will bind to a molecule, such as AMPK, using statistical analysis and protein docking simulations. Most commonly, virtual screening methods compare the three-dimensional structure of a protein to those of small molecules in a library. Different strategies for modeling protein-molecule interactions are used, although it is common to employ algorithms which simulate binding energies between atoms, including hydrogen bonds, electrostatic forces, and van-der walls interactions.
  • virtual screening methods can scan libraries of more than a million compounds and return a short list of small molecules which are likely to be strong binders.
  • compositions suitable for administration typically comprise the AMPK modulator or activator with or without a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal compounds, isotonic and absorption delaying compounds, and the like, compatible with pharmaceutical administration. Suitable carriers are described in the most recent edition of Remington's Pharmaceutical Sciences, a standard reference text in the field, which is incorporated herein by reference.
  • Such carriers or diluents include, but are not limited to, water, saline, Ringer's solutions, dextrose solution, and 5% human serum albumin. Liposomes and non-aqueous vehicles such as fixed oils may also be used.
  • the use of such media and compounds for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or compound is incompatible with the active compound, use thereof in the compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions.
  • a pharmaceutical composition of the invention is formulated to be compatible with its intended route of administration.
  • routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (i.e., topical), transmucosal, and rectal administration.
  • Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial compounds such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating compounds such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetates, citrates or phosphates, and compounds for the adjustment of tonicity such as sodium chloride or dextrose.
  • the pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
  • the parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
  • compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • suitable carriers include physiological saline, bacteriostatic water,
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal compounds, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
  • isotonic compounds for example, sugars, polyalcohols such as manitol, sorbitol, sodium chloride in the composition.
  • Prolonged absorption of the injectable compositions can be brought about by including in the composition a compound, which delays absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions can be prepared by incorporating the AMPK modulator or AMPK activator compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • Oral compositions generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding compounds, and/or adjuvant materials can be included as part of the composition.
  • the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating compound such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening compound such as sucrose or saccharin; or a flavoring compound such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating compound such as alginic acid, Primogel, or corn starch
  • a lubricant such as magnesium stearate or Sterotes
  • a glidant such as colloidal silicon dioxide
  • Systemic administration can also be by transmucosal or transdermal means.
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fasidic acid derivatives.
  • Transmucosal administration can be accomplished through the use of nasal sprays or suppositories.
  • the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.
  • the AMPK modulators and AMPK activators of the invention can also be prepared as pharmaceutical compositions in the form of suppositories (e.g., with conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery.
  • the compounds can be prepared for use in conditioning or treatment of ex vivo explants or implants.
  • the AMPK modulator compounds or AMPK activator compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • a controlled release formulation including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and poly lactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art.
  • the materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals.
  • the present invention also contemplates pharmaceutical compositions and formulations for co-administering the AMPK modulators or AMPK activators of the invention with one or more additional active agents.
  • the one or more additional active agents can include other agents or therapies for treating a kidney disease or disorder.
  • the one or more additional active agents can also include other therapies relating to the underlying disease or condition that results in or is involved in or relates to the the kidney disease or disorder.
  • the invention provides for both prophylactic and therapeutic methods of treating a subject at risk of or having polycystic kidney disease (PKD) using the AMPK modulators or AMPK activators of the invention.
  • PPD polycystic kidney disease
  • Polycystic kidney diseases are a group of genetic disorders in which clusters of cysts develop primarily within the kidneys.
  • ADPKD autosomal dominant polycystic kidney disease
  • ARPKD autosomal recessive polycystic kidney disease
  • ADPKD is the most common form of the disease, and signs and symptoms of ADPKD typically develop in adulthood.
  • the invention provides methods of treating autosomal dominant polycystic kidney disease (ADPKD).
  • the invention provides methods of treating autosomal recessive polycystic kidney disease (ARPKD).
  • ARPKD autosomal recessive polycystic kidney disease
  • the invention provides methods for treating nephronophthisis.
  • the invention provides methods for treating medullary cystic kidney disease.
  • the invention provides methods for treating multicystic renal dysplasia.
  • the invention provides methods for treating medullary sponge kidney.
  • the invention provides methods for treating glomerulocystic kidney disease.
  • the invention provides methods for treating Bardet-Biedl syndrome.
  • the invention provides methods for treating Joubert syndrome.
  • the invention provides methods for treating Meckel-Gruber syndrome.
  • the invention provides methods for treating MODY-5 syndrome.
  • Polycystic kidney disease is typically diagnosed using an ultrasound exam, a computerized tomography (CT) scan, or a magnetic resonance imaging (MRI) scan.
  • CT computerized tomography
  • MRI magnetic resonance imaging
  • Subjects having PKD commonly experience kidney failure, as well as high blood pressure.
  • Symptoms of PKD include high blood pressure, back or side pain, headache, increase in abdomen size, blood in urine, frequent urination, kidney stones, kidney failure, urinary tract infections, and/or kidney infections.
  • the invention provides methods for preventing or treating the symptoms associated with polycystic kidney diseases.
  • the AMPK modulators and AMPK activators of the invention can be administered in vitro (e.g., by culturing the cell and adding the AMPK modulator or AMPK activator compound) or, alternatively, in vivo (e.g., by administering the compound to a subject).
  • the invention provides methods of treating an individual afflicted with PKD.
  • Effective dosages and schedules for administering the compositions of the invention may be determined empirically, and making such determinations is within the skill in the art.
  • the dosage ranges for the administration of the compositions are those large enough to produce the desired effect in which the symptoms/disorder are/is affected.
  • the dosage should not be so large as to cause adverse side effects, such as unwanted cross- reactions, anaphylactic reactions, and the like.
  • the dosage will vary with the age, condition, sex and extent of the disease in the patient, route of administration, or whether other drugs are included in the regimen, and can be determined by one of skill in the art.
  • the dosage can be adjusted by the individual physician in the event of any counterindications.
  • Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days.
  • Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products. For example, in certain embodiments, a dosage of 0.0001 to 10,000 mg/kg body weight is administered to the subject per day. In other embodiments, the administered dosage is from 1 to 100 mg/kg body weight per day.
  • the AMPK modulator or AMPK activator is administered to the subject orally.
  • the AMPK modulator or AMPK activator of the invention may also be administered to the subject topically, enterally, or parenterally.
  • a AMPK modulator or AMPK activator of the invention is administered to a subject that has been identified as having PKD.
  • the invention provides methods for preventing or treating PKD, the method comprising selecting a subject having polycystic kidney disease or at risk for having polycystic kidney disease, and administering an AMPK modulator or an AMPK activator of the invention to the subject.
  • the compositions disclosed herein may be administered prophylactically to patients or subjects who are at risk for developing PKD.
  • the invention provides methods for determining the level of AMPK modulator or AMPK activation in a subject having polycystic kidney disease, the method comprising administering to the subject an AMPK modulator or an AMPK activator of the invention, obtaining a sample from the subject, and measuring the level of expression of a biomarker of AMPK modulation or AMPK activation in the sample from the subject.
  • the level of expression of the biomarker is compared to a control sample.
  • the control sample is a sample from the subject before administration of the AMPK modulator or AMPK activator.
  • a decrease in the level of a biomarker in the sample from the subject as compared to the control sample indicates that the AMPK modulator or AMPK activator is effective in treating or preventing PKD in the subject.
  • an increase in the level of a biomarker in the sample from the subject as compared to the control sample indicates that the AMPK modulator or AMPK activator is effective in treating or preventing PKD in the subject.
  • biomarkers of AMPK activation include branched chain amino acids, such as valine, leucine, or isoleucine, tyrosine, phenylalanine, acylcarnitine intermediates, insulinlike growth factor-binding protein 1 (IGFBP1), a citric acid cycle intermediate, citrulline, etc.
  • IGFBP1 insulinlike growth factor-binding protein 1
  • kits and pharmaceutical packages that are drawn to reagents or components that can be used in practicing the methods disclosed herein.
  • the kits can include any material or combination of materials discussed herein or that would be understood to be required or beneficial in the practice of the disclosed methods.
  • the kits could include an AMPK modulator or an AMPK activator of the invention, or one or more additional active agents.
  • a kit can include a set of instructions for using the components of the kit for its therapeutic and/or diagnostic purposes, such as for prevention or treatment of polycystic kidney disease (PKD).
  • PPD polycystic kidney disease

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Abstract

L'invention concerne des méthodes de traitement de la polykystose rénale (PKD) chez un sujet, comprenant l'administration d'un modulateur ou d'un activateur de 5'-adénosine monophosphate protéine kinase activée par l'AMP (AMPK). L'invention concerne également des kits comprenant un modulateur ou des activateurs de l'AMPK et les instructions pour leur utilisation pour le traitement de la PKD.
PCT/CA2016/050862 2015-07-23 2016-07-22 Méthodes de traitement et de prévention de la polykystose rénale (pkd) au moyen de modulateurs et d'activateurs de la protéine kinase activée par l'amp (ampk) Ceased WO2017011917A1 (fr)

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US201562196063P 2015-07-23 2015-07-23
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021198506A1 (fr) 2020-04-02 2021-10-07 Poxel Utilisation d'un dérivé de thiénopyridone dans le traitement de la polykystose rénale autosomique dominante (adpkd)
WO2024189592A1 (fr) 2023-03-16 2024-09-19 Kyoto Prefectural Public University Corporation Sephin1 et composés associés pour le traitement de maladies et de troubles susceptibles d'être traités par activation d'ampk et/ou inhibition de chop

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050038068A1 (en) * 2003-05-16 2005-02-17 Iyengar Rajesh R. Thienopyridones as AMPK activators for the treatment of diabetes and obesity
WO2011080277A1 (fr) * 2009-12-29 2011-07-07 Poxel Activateurs thiéno [2,3-b] pyridinedione de l'ampk et utilisations thérapeutiques de ceux-ci
WO2013153479A2 (fr) * 2012-04-10 2013-10-17 Pfizer Inc. Composés d'indole et d'indazole qui activent l'ampk

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050038068A1 (en) * 2003-05-16 2005-02-17 Iyengar Rajesh R. Thienopyridones as AMPK activators for the treatment of diabetes and obesity
WO2011080277A1 (fr) * 2009-12-29 2011-07-07 Poxel Activateurs thiéno [2,3-b] pyridinedione de l'ampk et utilisations thérapeutiques de ceux-ci
WO2013153479A2 (fr) * 2012-04-10 2013-10-17 Pfizer Inc. Composés d'indole et d'indazole qui activent l'ampk

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
IRAZABAL, MARIA V ET AL.: "Experimental therapies and ongoing clinical trials to slow down progression of ADPKD", CURRENT HYPERTENSION REVIEWS, vol. 9, no. 1, March 2013 (2013-03-01), pages 44 - 59, XP055329534 *
MCCARTY, M.F. ET AL.: "Activation of AMP-activated kinase as a strategy for managing autosomal dominant polycystic kidney disease", MEDICAL HYPOTHESES, vol. 73, no. 6, 2009, pages 1008 - 1010, XP026775113 *
PASTOR-SOLER ET AL.: "AMP-activated protein kinase regulation of kidney tubular transport", CURRENT OPIN NEPHROL HYPERTENS, vol. 21, 2012, pages 523 - 533 *
PATHOMTHONGTAWEECHAI ET AL.: "Pulmonary, gastrointestinal and urogenital pharamacology: Pranlukast inhibits renal epithelial cyst progression via activation of AMP-activated protein kinase", EUROPEAN JOURNAL OF PHARMACOLOGY, vol. 724, 2014, pages 67 - 76, XP028607136 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021198506A1 (fr) 2020-04-02 2021-10-07 Poxel Utilisation d'un dérivé de thiénopyridone dans le traitement de la polykystose rénale autosomique dominante (adpkd)
CN115361949A (zh) * 2020-04-02 2022-11-18 博希尔公司 噻吩并吡啶酮衍生物在治疗常染色体显性多囊肾病adpkd中的用途
JP2023510039A (ja) * 2020-04-02 2023-03-10 ポクセル 常染色体優性多発性嚢胞腎（ａｄｐｋｄ）の処置におけるチエノピリドン誘導体の使用
JP7366290B2 (ja) 2020-04-02 2023-10-20 ポクセル 常染色体優性多発性嚢胞腎（ａｄｐｋｄ）の処置におけるチエノピリドン誘導体の使用
US12310949B2 (en) 2020-04-02 2025-05-27 Poxel Use of a thienopyridone derivative in the treatment of autosomal dominant polycystic kidney disease (ADPKD)
WO2024189592A1 (fr) 2023-03-16 2024-09-19 Kyoto Prefectural Public University Corporation Sephin1 et composés associés pour le traitement de maladies et de troubles susceptibles d'être traités par activation d'ampk et/ou inhibition de chop

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