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WO2020055687A1 - Méthodes de traitement de l'hypertension pulmonaire - Google Patents

Méthodes de traitement de l'hypertension pulmonaire Download PDF

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Publication number
WO2020055687A1
WO2020055687A1 PCT/US2019/049943 US2019049943W WO2020055687A1 WO 2020055687 A1 WO2020055687 A1 WO 2020055687A1 US 2019049943 W US2019049943 W US 2019049943W WO 2020055687 A1 WO2020055687 A1 WO 2020055687A1
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substituted
mast cell
cell stabilizer
prolyl hydroxylase
hif prolyl
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Randi B. Silver
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Cornell University
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Cornell University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4741—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having oxygen as a ring hetero atom, e.g. tubocuraran derivatives, noscapine, bicuculline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system

Definitions

  • Pulmonary hypertension is a progressive disease of various origins associated with a poor prognosis and results in right heart dysfunction. In all its variant presentations, it is estimated to affect up to 100 million people worldwide. Pulmonary hypertension is defined as a lung disorder characterized by increased pressure in the pulmonary artery. The pulmonary artery carries oxygen-poor blood from the lower chamber on the right side of the heart (right ventricle) to the lungs where it picks up oxygen. Pulmonary hypertension is present when the blood pressure in the circulation of the lungs is measured at greater than 25 mm of mercury (Hg) at rest or 30 mm Hg during exercise.
  • Hg 25 mm of mercury
  • Pulmonary arterial hypertension (PAH), a category of chronic pulmonary hypertension, includes a variety of diseases that share several pathophysiological, histological, and prognostic features.
  • PAH is a life-threatening disease that is characterized by increased pulmonary vascular resistance owing to progressive vascular remodeling, which can ultimately lead to right heart failure and death (Schermuly RT. et al., Nature Reviews Cardiology, 2011; 8: 443-455).
  • PAH is characterized by excessive pulmonary vasoconstriction and abnormal vascular remodeling where inflammation plays a major role. Specifically, the vasoconstriction, remodeling of the pulmonary vessel wall marked by intimal fibrosis and increased medial thickness, pulmonary arteriolar occlusion,
  • An aspect of this disclosure is directed to a method for treating pulmonary hypertension (PAH) comprising administering to a subject in need of such treatment an effective amount of a mast cell stabilizer.
  • PAH pulmonary hypertension
  • the mast cell stabilizer is selected from the group consisting of cromoglicic acid, ketotifen, olopatadine, rupatadine, mepolizumab, omalizumab, pemirolast, quercetin, nedocromil, azelastine, tranilast, palmitoylethanolamide, and vitamin
  • the mast cell stabilizer is nedocromil. [0008] In some embodiments, the mast cell stabilizer is administered systemically. In some embodiments, the mast cell stabilizer is administered locally to the lung.
  • Another aspect of this disclosure is directed to a method for treating pulmonary hypertension comprising administering to a subject in need of such treatment an effective amount of a HIF prolyl hydroxylase domain inhibitor.
  • the HIF prolyl hydroxylase domain inhibitor is selected from the group consisting of Roxadustat (RXD) (FG-4592), Vadadustat (AKB-6548),
  • Daprodustat (GSK- 1278863), and Molidustat (BAY 85-3934).
  • the HIF prolyl hydroxylase domain inhibitor is administered systemically. In some embodiments, the HIF prolyl hydroxylase domain inhibitor is administered locally to the lung.
  • the HIF prolyl hydroxylase domain inhibitor is RXD.
  • Another aspect of this disclosure is directed to a method for treating pulmonary hypertension comprising administering to a subject in need of such treatment a
  • combination therapy comprising an effective amount of a mast cell stabilizer and an effective amount of a HIF prolyl hydroxylase domain inhibitor.
  • the mast cell stabilizer and the HIF prolyl hydroxylase domain inhibitor are administered as one composition. In some embodiments, the mast cell stabilizer and the HIF prolyl hydroxylase domain inhibitor are administered separately. In some embodiments, the mast cell stabilizer and the HIF prolyl hydroxylase domain inhibitor are administered consecutively. In some embodiments, the mast cell stabilizer and the HIF prolyl hydroxylase domain inhibitor are administered simultaneously.
  • the mast cell stabilizer is selected from the group consisting of cromoglicic acid, ketotifen, olopatadine, rupatadine, mepolizumab, omalizumab, pemirolast, quercetin, nedocromil, azelastine, tranilast, palmitoylethanolamide, and vitamin
  • the mast cell stabilizer is nedocromil. [0017] In some embodiments, the mast cell stabilizer is administered systemically. In some embodiments, the mast cell stabilizer is administered locally to the lung.
  • the HIF prolyl hydroxylase domain inhibitor is selected from the group consisting of Roxadustat (RXD) (FG-4592), Vadadustat (AKB-6548),
  • Daprodustat (GSK- 1278863), and Molidustat (BAY 85-3934).
  • the HIF prolyl hydroxylase domain inhibitor is RXD.
  • the HIF prolyl hydroxylase domain inhibitor is administered systemically. In some embodiments, the HIF prolyl hydroxylase domain inhibitor is administered locally to the lung.
  • Another aspect of this disclosure is directed to a use of a mast cell stabilizer for the manufacture of a medicament for use in the treatment of pulmonary hypertension.
  • Another aspect of this disclosure is directed to a use of a HIF prolyl hydroxylase domain inhibitor for the manufacture of a medicament for use in the treatment of pulmonary hypertension.
  • Another aspect of this disclosure is directed to a use of a mast cell stabilizer and a HIF prolyl hydroxylase domain inhibitor for the manufacture of a medicament for use in the treatment of pulmonary hypertension.
  • the mast cell stabilizer is selected from the group consisting of cromoglicic acid, ketotifen, olopatadine, rupatadine, mepolizumab, omalizumab, pemirolast, quercetin, nedocromil, azelastine, tranilast, palmitoylethanolamide, and vitamin
  • the mast cell stabilizer is nedocromil.
  • the mast cell stabilizer is administered systemically. In some embodiments, the mast cell stabilizer is administered locally to the lung. [0027] In some embodiments, the HIF prolyl hydroxylase domain inhibitor is selected from the group consisting of Roxadustat (RXD) (FG-4592), Vadadustat (AKB-6548),
  • Daprodustat (GSK- 1278863), and Molidustat (BAY 85-3934).
  • the HIF prolyl hydroxylase domain inhibitor is Roxadustat (RXD) (FG-4592).
  • the HIF prolyl hydroxylase domain inhibitor is administered systemically. In some embodiments, the HIF prolyl hydroxylase domain inhibitor is administered locally to the lung.
  • the pulmonary hypertension is pulmonary arterial hypertension (PAH).
  • PAH pulmonary arterial hypertension
  • the patent or application file contains at least one drawing executed in color.
  • FIGS. 1A - IB Mast cells are increased in pulmonary arteries with PAH.
  • FIGS. 2A - 2C Stabilizing mast cells prevents remodeling of the pulmonary artery (PA) wall associated with PAH (MCT-injected rats). Cross-sections of PA stained with Gomori's trichrome; collagen is stained blue.
  • A Untreated control (CON),
  • B MCT- injected, and
  • C MCT-injected + nedocromil (a mast cell stabilizer) -treated PAs. Line in each image shows thickness of PA wall. Viewed at 15c.
  • FIGS. 3A - 3B Treating PAH (monocrotaline (MCT) rats) with the mast cell stabilizer nedocromil (+ treatment) reduced interstitial pulmonary fibrosis as evidenced by its reversed effect on elastance (A) and compliance (B).
  • FIGS. 4A - 4C Stabilizing Mast Cells Prevents Abnormal Flow Velocity in PAH.
  • Mast cell stabilization (C) prevents PA wave reflection typical of PAH (white arrows, B). Mast-cell stabilizer treated samples more closely resemble untreated controls (CON, A).
  • FIGS. 5A - 5D Association of Increased Mast Cell Number with Excess Collagen Deposition in Right Ventricle of MCT-Treated Rats.
  • RV right ventricle
  • A Control (CON) rat stained for mast cells (MSc).
  • B PAH (monocrotaline (MCT)-injected ) rat stained for mast cells.
  • C Control (CON) rat stained for collagen.
  • D PAH (monocrotaline (MCT)-injected) rat stained for collagen.
  • CON right ventricle
  • the MCT-injected rat also has abundant collagen deposition as shown by the blue staining in (D) whereas there was minimal collagen staining in CON (C).
  • the spatial distribution of mast cells correlated with the collagen stained regions of the RV in the MCT-rat (consecutive sections C and D).
  • FIGS. 6A - 6C Treatment with a mast cell stabilizer (nedocromil) prevents right ventricular dilation (right ventricular overload) and its effect on the interventricular septum in PAH (monocrotaline (MCT))-injected rat (28d).
  • A Echocardiogram in B-mode on control (CON) rats.
  • B Echocardiogram in B-mode on MCT-injected (MCT) rats.
  • C Echocardiogram in B-mode on PAH (monocrotaline (MCT)) and mast cell stabilizer (nedocromil) -injected rat.
  • FIG. 7 Blocking the ANG II ATiR with the active metabolite of losartan (ATiR- B) inhibits the mast cell-induced contraction of PA from PAH (monocrotaline (MCT))-rats. The contraction is expressed as percentage of the response to K+ (60 mM) in PA rings from CON and MCT-injected rats. ** p ⁇ 0.0l.
  • FIG. 9 The HIF Stabilizer Roxadustat (RXD) prevents mast cells from
  • pulmonary artery PA
  • Therapeutic dosing with the hypoxia inducible factor (HIF) stabilizer roxadustat (10 mg/kg), prevents the increase in pulmonary artery (PA) mast cell number in neonatal hyperoxia- induced PAH. **P ⁇ 0.0l between room air and high oxygen, N 3 mice/group. All other comparisons to room air were not significant.
  • RA room air
  • HO High Oxygen
  • RXD Roxadustat (a HIF prolyl hydroxylase domain inhibitor and HIF stabilizer).
  • FIG. 10 HIF stabilization with Roxadustat (RXD) (10 mg/kg) decreases the magnitude of PA contraction in rings from mice with PAH (exposed to neonatal high oxygen (HO)). Contractile response to C48/80 (300pg/ml) expressed in mg in PA rings from age-matched room air (RA), high oxygen (HO)-exposed, and HO-exposed and RXD- treated (HO + RXD), mice.
  • RXD Roxadustat
  • FIGS. 12A - 12C HIF Stabilization Inhibits Right Ventricle Free Wall Thickness, a Marker of Hypertrophy, in Neonatal PAH.
  • A Room Air
  • B High Oxygen
  • C High Oxygen + HIF stabilizer.
  • FIG. 13 HIF Stabilization Inhibits Right Ventricular Remodeling Due to Neonatal PAH.
  • FIG. 14 Mast Cells are Abundant in the Pulmonary Arteries of Premature Babies with Bronchopulmonary Dysplasia (BPD) and PAH. Representative sections of pulmonary artery from an infant who died from BPD-associated PAH were stained for mast cells with HRP-avidin. Mast cells are stained brown as seen at 20x and in the inlay, 40x, where granules and nucleus are visible.
  • BPD Bronchopulmonary Dysplasia
  • One aspect of the present disclosure is directed to a method for treating pulmonary hypertension by administering to a subject in need of such treatment an effective amount of a mast cell stabilizer.
  • administering to a subject an effective amount of a mast cell stabilizer prevents or reduces the blood pressure in the arteries of lungs and the right side of the heart.
  • the mast cell stabilizer is administered locally to the lungs.
  • the mast cell stabilizer is administered as an aerosol.
  • the aerosol comprising the mast cell stabilizer is administered using a dose metered inhaler or a nebulizer.
  • the mast cell stabilizer is administered systemically.
  • an effective amount of a mast cell stabilizer is about 0.2 mg/kg to 100 mg/kg. In other embodiments, the effective amount of a mast cell stabilizer is about 0.2mg/kg, 0.5mg/kg, lmg/kg, 8mg/kg, lOmg/kg, 20mg/kg, 30mg/kg, 40mg/kg, 50mg/kg, 60mg/kg, 70mg/kg, 80mg/kg, 90mg/kg, lOOmg/kg, l50mg/kg, l75mg/kg or 200mg/kg of mast cell stabilizer.
  • Another aspect of the present disclosure is directed to a method for treating pulmonary hypertension by administering to a subject in need of such treatment an effective amount of a HIF prolyl hydroxylase domain inhibitor.
  • administering to a subject an effective amount of a HIF prolyl hydroxylase domain inhibitor reduces the blood pressure in the arteries of lungs and the right side of the heart.
  • the HIF prolyl hydroxylase domain inhibitor is administered locally. In some embodiments, the HIF prolyl hydroxylase domain inhibitor is
  • the aerosol comprising the HIF prolyl hydroxylase domain inhibitor is administered using a dose metered inhaler or a nebulizer.
  • the HIF prolyl hydroxylase domain inhibitor is administered systemically.
  • an effective amount of a HIF prolyl hydroxylase domain inhibitor is about 0.2 mg/kg to 100 mg/kg. In other embodiments, the effective amount of a HIF prolyl hydroxylase domain inhibitor is about 0.2mg/kg, 0.5mg/kg, lmg/kg, 8mg/kg, lOmg/kg, 20mg/kg, 30mg/kg, 40mg/kg, 50mg/kg, 60mg/kg, 70mg/kg, 80mg/kg, 90mg/kg, lOOmg/kg, l50mg/kg, l75mg/kg or 200mg/kg of HIF prolyl hydroxylase domain inhibitor.
  • a third aspect of the present disclosure is directed to a method for treating pulmonary hypertension by administering to a subject in need of such treatment a combination therapy comprising an effective amount of a mast cell stabilizer and an effective amount of a HIF prolyl hydroxylase domain inhibitor.
  • administering to a subject a combination therapy comprising an effective amount of a mast cell stabilizer and an effective amount of a HIF prolyl hydroxylase domain inhibitor prevents or reduces high blood pressure in the arteries of lungs and the right side of the heart.
  • the mast cell stabilizer and the HIF prolyl hydroxylase domain inhibitor are administered in one composition. In some embodiments, the mast cell stabilizer and the HIF prolyl hydroxylase domain inhibitor are administered consecutively. In some embodiments, the mast cell stabilizer and the HIF prolyl hydroxylase domain inhibitor are administered separately. In some embodiments, the mast cell stabilizer and the HIF prolyl hydroxylase domain inhibitor are administered simultaneously.
  • the mast cell stabilizer and the HIF prolyl hydroxylase domain inhibitor are administered in one composition.
  • a composition comprising a mast cell stabilizer and a HIF prolyl hydroxylase domain inhibitor is not administered to the subject continuously; rather it is administered intermittently.
  • intermittent administration is performed once every other day, every three days, every four days, every five days, or once a week.
  • intermittent administration is performed once every hour, every two hours, every three hours, every six hours, every ten hours, or every twelve hours.
  • the subject in need of treatment is a neonatal (newborn) subject.
  • mast cell stabilizer refers to an agent which prevents mast cells from breaking open and releasing chemicals (e.g., histamine, proteoglycans, serotonin, and serine proteases) that help cause inflammation (aka.
  • chemicals e.g., histamine, proteoglycans, serotonin, and serine proteases
  • the mast cell stabilizer is a small molecule.
  • small molecule compound refers to small organic chemical compound, generally having a molecular weight of less than 2000 daltons, 1500 daltons, 1000 daltons, 800 daltons, or 600 daltons.
  • the mast cell stabilizer comprises compounds including, but not limited to
  • Cromoglycic acid (cromolyn) with the chemical formula C 23 H 16 O 11 and the chemical structure ketotifen with the chemical formula C 19 H 19 NOS and the chemical structure
  • the mast stabilizer is selected from the group consisting of Cromoglicic acid, Ketotifen, Olopatadine, Rupatadine, Mepolizumab, Omalizumab, Pemirolast, Quercetin, Nedocromil, Azelastine, Tranilast, Palmitoylethanolamide, and Vitamin D.
  • the mast cell stabilizer is nedocromil.
  • the mast cell stabilizer is ketotifen.
  • the mast cell stabilizer is administered locally. In some embodiments, the mast cell stabilizer is administered systemically.
  • the phrase "HIF prolyl hydroxylase domain inhibitor” refers to an agent that inhibits the activity of HIF hydroxylase or other enzymes in the 2-OG (2- oxoglutarate)-dependent dioxygenase enzyme superfamily having structural similarity and a common reaction mechanism with HIF hydroxylase.
  • An agent that inhibits HIF prolyl hydroxylase activity is any agent that reduces or otherwise modulates the activity of a HIF prolyl hydroxylase or related enzyme, such as C-P4H.
  • the HIF prolyl hydroxylase domain inhibitor is a small molecule.
  • the HIF prolyl hydroxylase domain inhibitor is selected from the group consisting of Roxadustat (RXD) (FG-4592), Vadadustat (AKB-6548),
  • Daprodustat (GSK- 1278863), and Molidustat (BAY 85-3934).
  • HIF prolyl hydroxylase domain inhibitors is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • Rl is selected from the group consisting of hydroxyl, alkoxy, substituted alkoxy, aryloxy, and substituted aryloxy;
  • R2 and R3 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, and substituted heteroaryl; or R2 and R3 together with the carbon atom to which they are attached form a cycloalkyl, substituted cycloalkyl, hererocycloalkyl, or substituted hererocycloalkyl;
  • R4 is selected from the group consisting of hydrogen, alkyl, and substituted alkyl
  • R5 is selected from the group consisting of hydroxyl, alkoxy, and substituted alkoxy;
  • R6 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cyano, halo, hydroxyl, alkoxy, substituted alkoxy, amino, substituted amino, arylozy, substituted arylozy, aminoacyl, substituted aminoacyl, cycloalkoxy, substituted cycloalkoxy, aryl, substituted aryl, aryloxy, substituted aryloxy, heterocycloalkyl, substituted heterocycloalkyl, heteroaryloxy, substituted heteroaryloxy, heteroaryl, and substituted heteroaryl; and
  • R7, R8, R9 and R10 are independently selected from the group consisting of hydrogen, halo, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkoxy, substituted alkoxy, aryloxy, and substituted aryloxy.
  • R6 is alkyl. In another embodiment, the alkyl at R6 is methyl.
  • R5 is hydroxyl
  • R8 is aryloxy
  • R6 is methyl and R5 is hydroxyl.
  • alkyl refers to a straight or branched, saturated hydrocarbon group having 1 to 10 carbon atoms, more particularly from 1 to 5 carbon atoms, and even more particularly 1 to 3 carbon atoms.
  • Representative alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, n-pentyl, and the like.
  • substituted alkyl refers to an alkyl group of from 1 to 10 carbon atoms, more particularly 1 to 5 carbon atoms, and having from 1 to 5 substituents, preferably 1 to 3 substituents, each of which substituents is independently selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, oxo, thioxo, carboxyl, carboxyl esters, cycloalkyl, substituted cycloalkyl, thio, alkylthio, substituted alkylthio, arylthio, substituted arylthi
  • NR1 lS(0)2 NR1 l-heteroaryl,— NR1 lS(0)2— NR1 l-substituted heteroaryl,—
  • NR1 lS(0)2 NR11 -heterocyclic
  • NR1 lS(0)2 NR1 l-substituted heterocyclic
  • each Rl 1 is independently selected from hydrogen or alkyl.
  • Representative substituted alkyl groups include trifluoromethyl, benzyl, pyrazol-l-ylmethyl and the like.
  • alkoxy refers to the group “alkyl-0— ,” which includes, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, t-butoxy, sec-butoxy, n- pentoxy, and the like.
  • substituted alkoxy refers to the group “substituted alkyl-0— ".
  • 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)— , aryl-C(O)— , substituted aryl- C(O)— , heteroaryl-C(O)— , substituted heteroaryl-C(O), heterocyclic-C(O)— , and substituted heterocyclic-C(O)— , provided that a nitrogen atom of the heterocyclic or substituted heterocyclic
  • aminoacyl or “amide”, or the prefix “carbamoyl,” “carboxamide,” “substituted carbamoyl” or “substituted carboxamide” refers to the group— C(0)NRl2Rl2, wherein each R12 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; or wherein each R12 is joined to form together with the nitrogen atom a heterocyclic or substituted heterocyclic, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, ary
  • acyloxy refers to the groups 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-C(0)0— , cycloalkyl-C(0)0— , substituted cycloalkyl-C(0)0— , heteroaryl-C(0)0— , substituted heteroaryl-C(0)0— , heterocyclic- C(0)0— , and substituted heterocyclic-C(0)0— , wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, substituted heteroary
  • heterocyclic are as defined herein.
  • Representative alkenyl groups include vinyl (ethen-l-yl), allyl, but-3-enyl and the like.
  • substituted alkenyl refers to alkenyl groups having from 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, halogen, hydroxyl, nitro, carboxyl, carboxyl esters, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic.
  • This term includes both E (trans) and Z (cis) isomers as appropriate. It also includes mixtures of both E and Z components.
  • alkynyl refers to acetylenic unsaturated monovalent hydrocarbyl groups having from 2 to 6 carbon atoms, and preferably 2 to 3 carbon atoms, and having at least 1, and preferably from 1 to 2 sites of acetylenic (— CoC— ) unsaturation.
  • Representative alkynyl groups include ethyn-l-yl, propyn-l-yl, propyn-2-yl, and the like.
  • amino refers to the group— NH2.
  • substituted amino refers to the group— NR13R13, wherein each R13 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted
  • Representative substituted amino groups include phenylamino, methylphenylamino, and the like.
  • Representative substituted amino groups include (ethanic acid-2-yl)amino, and the like.
  • acylamino refers to the groups— NRl4C(0)alkyl,—
  • NRl4C(0)heteroaryl — NRl4C(0)substituted heteroaryl,— NRl4C(0)heterocyclic, and — NRl4C(0)substituted heterocyclic, wherein R14 is hydrogen or alkyl, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
  • heterocyclic and substituted heterocyclic are defined herein.
  • oxycarbonylamino refers to the groups— NRl5C(0)0-alkyl,—
  • NRl5C(0)0-substituted alkyl — NRl5C(0)0-alkenyl,— NRl5C(0)0-substituted alkenyl,— NRl5C(0)0-alkynyl,— NRl5C(0)0-substituted alkynyl,— NRl5C(0)0- cycloalkyl,— NRl5C(0)0-substituted cycloalkyl,— NRl5C(0)0-aryl,— NRl5C(0)0- substituted aryl,— NRl5C(0)0-heteroaryl,— NRl5C(0)0-substituted heteroaryl,— NRl5C(0)0-heterocyclic, and— NRl5C(0)0-substituted heterocyclic, wherein R15 is hydrogen or alkyl, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycl
  • oxythiocarbonylamino refers to the groups— NRl6C(S)0-alkyl,— NRl6C(S)0-substituted alkyl,— NRl6C(S)0-alkenyl,— NRl6C(S)0-substituted alkenyl, — NRl6C(S)0-alkynyl,— NRl6C(S)0-substituted alkynyl,— NRl6C(S)0-cycloalkyl,— NRl6C(S)0-substituted cycloalkyl,— NRl6C(S)0-aryl,— NRl6C(S)0-substituted aryl,
  • R16 is hydrogen or alkyl, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
  • aminocarbonyloxy or the prefix “carbamoyloxy” or “substituted carbamoyloxy,” refers to the groups— 0C(0)NRl7Rl7, wherein each R17 is
  • each R17 is joined to form, together with the nitrogen atom, a heterocyclic or substituted heterocyclic, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; or wherein each R17 is joined to form, together with the nitrogen atom, a heterocyclic or substituted heterocyclic, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted
  • heterocyclic are as defined herein.
  • aminocarbonylamino refers to the group— NRl8C(0)— NR18R18, wherein each R18 is independently selected from the group consisting of hydrogen and alkyl.
  • aminothiocarbonylamino refers to the group— NRl9C(S)— NR19R19, wherein each R19 is independently selected from the group consisting of hydrogen and alkyl.
  • aryl refers to a monovalent aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) which condensed rings may or may not be aromatic (e.g., 2-benzoxazolinone, 2H-l,4-benzoxazin-3(4H)-one-7-yl, and the like) provided that the point of attachment is the aryl group.
  • Preferred aryls include phenyl and naphthyl.
  • Representative substituted aryl groups include 4-fluorophenyl, 3-methoxyphenyl, 4-t-butylphenyl, 4-trifluoromethylphenyl, 2-trifluoromethoxyphenyl, 3- trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 4- chlorophenyl, 2-chloro-6-fluorophenyl, 2,4-dichlorophenyl, 4-methoxyphenyl, 3- cyanophenyl, 4-cyanophenyl, 4-phenoxyphenyl, 4-methanesulfonylphenyl, biphenyl-4-yl, and the like.
  • aryloxy refers to the group aryl-0— that includes, by way of example, phenoxy, naphthoxy and the like.
  • substituted aryloxy refers to substituted aryl-0— groups.
  • aryloxyaryl refers to the group -aryl-O-aryl.
  • substituted aryloxyaryl refers to aryloxyaryl groups substituted with from 1 to 3 substituents on either or both aryl rings as defined above for substituted aryl.
  • carboxyl ester 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)P-cycloalkyl,— C(0)0-substituted cycloalkyl,— C(0)0-aryl, — C(0)0 -substituted aryl,— C(0)0-heteroaryl,— C(0)0-substituted heteroaryl,— C(0)0-heterocyclic, and— C(0)0-substituted heterocyclic.
  • cyano refers to the group— CN.
  • cycloalkyl refers to a saturated or an unsaturated but nonaromatic cyclic alkyl groups of from 3 to 10, 3 to 8 or 3 to 6 carbon atoms having single or multiple cyclic rings including, by way of example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, cyclohexenyl, and the like.
  • cycloalkylene and "substituted cycloalkylene” refer to divalent cycloalkyl and substituted cycloalkyl groups as defined above.
  • cycloalkoxy refers to— O-cycloalkyl groups.
  • substituted cycloalkoxy refers to— O-substituted cycloalkyl groups.
  • halo or halogen refers to fluoro, chloro, bromo, and iodo.
  • hydroxy or "hydroxyl” refers to the group— OH.
  • heteroaryl refers to an aromatic ring of from 1 to 15 carbon atoms, preferably from 1 to 10 carbon atoms, and 1 to 4 heteroatoms within the ring selected from the group consisting of oxygen, nitrogen, and sulfur.
  • Such heteroaryl groups can have a single ring (e.g., pyridinyl, furyl, or thienyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl) provided the point of attachment is through a ring containing the heteroatom and that ring is aromatic.
  • the nitrogen and/or sulfur ring atoms can optionally be oxidized to provide for the N-oxide or the sulfoxide, and sulfone derivatives.
  • Representative heteroaryl groups include pyridinyl, pyrimidinyl, pyrrolyl, pyrazolyl, indolyl, thiophenyl, thienyl, furyl, and the like.
  • substituted heteroaryl refers to heteroaryl groups that are substituted with from 1 to 3 substituents selected from the same group of substituents defined for substituted aryl.
  • Representative substituted heteroaryl groups include 5-fluoro- pyridin-3-yl, l-benzyl-lH-[l,2,3]triazol-4-yl, 5-bromo-furan-2-yl, trifluoromethyl-2H- pyrazol-3-yl, and the like.
  • heteroaryloxy refers to the group— O-heteroaryl
  • substituted heteroaryloxy refers to the group— O-substituted heteroaryl.
  • heterocyclyl or “heterocyclic” refers to a saturated or unsaturated
  • (but not aromatic) group having a single ring or multiple condensed rings, from 1 to 10 carbon atoms, and from 1 to 4 hetero atoms selected from the group consisting of nitrogen, sulfur or oxygen within the ring, wherein in fused ring systems, one or more of the rings can be aryl or heteroaryl provided that the point of attachment is at the heterocycle.
  • the nitrogen and/or sulfur ring atoms can optionally be oxidized to provide for the N-oxide or the sulfoxide, and sulfone derivatives.
  • substituted heterocyclyl or “substituted heterocyclic” refers to heterocycle groups that are substituted with from 1 to 3 of the same substituents as defined for substituted cycloalkyl.
  • 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, l,2,3,4-tetrahydroisoquino
  • sulfonyl refers to the group— S(0) 2 H.
  • substituted sulfonyl refers to the group— S0 2 -alkyl,— S0 2 - substituted alkyl,— S0 2 -alkenyl,— S0 2 -substituted alkenyl,— S0 2 -alkynyl,— S0 2 - substituted alkynyl,— S0 2 -cycloalkyl,— S0 2 -substituted cycloalkyl,— S0 2 -cycloalkenyl, — S0 2 -substituted cycloalkenyl,— S0 2 -aryl,— S0 2 -substituted aryl,— S0 2 -heteroaryl,— S0 2 -substituted heteroaryl,— S0 2 -heterocyclic,— S0 2 - substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl,
  • heterocyclyloxy refers to the group— O-heterocyclic
  • substituted heterocyclyloxy refers to the group— O-substituted heterocyclic
  • alkylsulfanyl refers to the groups— S-alkyl, wherein alkyl is as defined above.
  • substituted alkylthio refers to the group— S-substituted alkyl, wherein substituted alkyl is as defined above.
  • cycloalkylthio or "cycloalkylsulfanyl” refers to the groups— S- cycloalkyl wherein cycloalkyl is as defined above.
  • substituted cycloalkylthio refers to the group— S-substituted cycloalkyl wherein substituted cycloalkyl is as defined above.
  • arylthio or “arylsulfanyl” refers to the group— S-aryl
  • substituted arylthio refers to the group— S-substituted aryl, wherein aryl and substituted aryl are as defined above.
  • heteroarylthio or “heteroarylsulfanyl” refers to the group— S- heteroaryl
  • substituted heteroarylthio refers to the group— S-substituted heteroaryl, wherein heteroaryl and substituted heteroaryl are as defined above.
  • heterocyclicthio or “heterocyclicsulfanyl” refers to the group—
  • S-heterocyclic and "substituted heterocyclicthio" refers to the group— S-substituted heterocyclic wherein heterocyclic, and substituted heterocyclic are as defined above.
  • esters refers to the group— C(0)OR2l, wherein R21 is alkyl, substituted alkyl, aryl, or substituted aryl.
  • Rl and R5 are hydroxyl; R2, R3, R4, R7, R9, and R10 are hydrogen; R6 is methyl; and R8 is phenox, and the compound has a structure shown below in formula (II).
  • This molecule is also known as FG-4592 (aka. Roxadustat), which is an isoquinolone having the chemical name, N- [(4-hydroxy- l-methyl- 7-phenoxyisoquinolin-3-yl)carbonyl]glycine)].
  • FG-4592 (Roxadustat) is in phase 3 clinical trials for the treatment of anemia in chronic kidney disease with no untoward effects reported.
  • an effective amount of FG-4592 is an amount between 0.2 mg/kg and 20 mg/kg.
  • an effective dosage of FG-4592 (Roxadustat) is 0.2mg/kg, 0.5mg/kg, 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 7 mg/kg, 8mg/kg, 9 mg/kg, 10 mg/kg, 15 mg/kg, 18 mg/kg, or 20mg/kg.
  • FG-4592 (Roxadustat) analogue is used.
  • FG-4592 analogues are described in US Patents Nos: 9,701,647; 9,439,888; 7,863,292; and US Patent Application Nos: 13/186351 and 11/549571, which are all incorporated by reference in their entirety.
  • the HIF prolyl hydroxylase domain inhibitor is RXD (roxadustat).
  • the HIF prolyl hydroxylase domain inhibitor is administered locally. In some embodiments, the HIF prolyl hydroxylase domain inhibitor is administered systemically.
  • compositions comprising mast cell stabilizer or a HIF prolyl hydroxylase domain inhibitor
  • a mast cell stabilizer or a HIF prolyl hydroxylase domain inhibitor can be combined with a pharmaceutically acceptable carrier prior to administration.
  • pharmaceutically acceptable carriers means any of the standard pharmaceutical carriers. Examples of suitable carriers are well known in the art and may include, but are not limited to, any of the standard
  • compositions comprising such carriers are formulated by well-known conventional methods.
  • a mast cell stabilizer or a HIF prolyl hydroxylase domain inhibitor can be admixed with a pharmaceutically acceptable carrier to make a pharmaceutical preparation in any conventional form including, inter alia, a solid form such as tablets, capsules (e.g. hard or soft gelatin capsules), pills, cachets, powders, granules, and the like; a liquid form such as solutions, suspensions; or in micronized powders, sprays, aerosols and the like.
  • compositions of the present disclosure can be used in liquid, solid, tablet, capsule, pill, ointment, cream, nebulized or other forms as explained below.
  • the composition of the present disclosure may be administered by different routes of administration such as oral, oronasal, parenteral or topical.
  • Oral or “peroral” administration refers to the introduction of a substance into a subject's body through or by way of the mouth and involves swallowing or transport through the oral mucosa (e.g., sublingual or buccal absorption) or both.
  • oral mucosa e.g., sublingual or buccal absorption
  • Oronasal administration refers to the introduction of a substance into a subject's body through or by way of the nose and the mouth, as would occur, for example, by placing one or more droplets in the nose. Oronasal administration involves transport processes associated with oral and intranasal administration.
  • Parenteral administration refers to the introduction of a substance into a subject's body through or by way of a route that does not include the digestive tract.
  • Parenteral administration includes subcutaneous administration, intramuscular
  • administration transcutaneous administration, intradermal administration, intraperitoneal administration, intraocular administration, and intravenous administration.
  • Topical administration means the direct contact of a substance with tissue, such as skin or membrane, particularly the oral or buccal mucosa.
  • the pharmaceutical preparations of the present disclosure can be made up in any conventional form including, inter alia ,: (a) a solid form for oral administration such as tablets, capsules (e.g. hard or soft gelatin capsules), pills, sachets, powders, granules, and the like; (b) preparations for topical administrations such as solutions, suspensions, ointments, creams, gels, micronized powders, sprays, aerosols and the like.
  • a solid form for oral administration such as tablets, capsules (e.g. hard or soft gelatin capsules), pills, sachets, powders, granules, and the like
  • preparations for topical administrations such as solutions, suspensions, ointments, creams, gels, micronized powders, sprays, aerosols and the like.
  • compositions may be sterilized and/or may contain adjuvants such as preservatives, stabilizers, wetting agents, emulsifiers, salts for varying the osmotic pressure and/or buffers.
  • adjuvants such as preservatives, stabilizers, wetting agents, emulsifiers, salts for varying the osmotic pressure and/or buffers.
  • compositions are preferably prepared as ointments, tinctures, creams, gels, solution, lotions, sprays; aerosols and dry powder for inhalation, suspensions, shampoos, hair soaps, perfumes and the like.
  • any conventional composition can be utilized in this invention.
  • the composition containing the agents of this invention is in the form of an ointment, gel, cream, lotion, spray; aerosol or dry powder for inhalation.
  • the pharmaceutical preparation for topical administration to the skin can be prepared by mixing the aforementioned active ingredient with non-toxic, therapeutically inert, solid or liquid carriers customarily used in such preparation. These preparations generally contain 0.01 to 5.0 percent by weight, or 0.1 to 1.0 percent by weight, of the active ingredient, based on the total weight of the composition.
  • additives such as preservatives, thickeners, perfumes and the like conventional in the art of pharmaceutical compounding of topical preparation can be used.
  • conventional antioxidants or mixtures of conventional antioxidants can be incorporated into the topical preparations containing the aforementioned active agent.
  • the conventional antioxidants which can be utilized in these preparations are included N-methyl-a-tocopherolamine, tocopherols, butylated hydroxyanisole, butylated hydroxytoluene, ethoxyquin and the like.
  • Cream-based pharmaceutical formulations containing the active agent are composed of aqueous emulsions containing a fatty acid alcohol, semi- solid petroleum hydrocarbon, ethylene glycol and an emulsifying agent.
  • Ointment formulations containing the active agent in accordance with this invention comprise admixtures of a semi- solid petroleum hydrocarbon with a solvent dispersion of the active material.
  • Cream compositions containing the active ingredient for use in this invention preferably comprise emulsions formed from a water phase of a humectant, a viscosity stabilizer and water, an oil phase of a fatty acid alcohol, a semi-solid petroleum hydrocarbon and an emulsifying agent and a phase containing the active agent dispersed in an aqueous stabilizer-buffer solution.
  • Stabilizers may be added to the topical preparation. Any conventional stabilizer can be utilized in accordance with this invention.
  • fatty acid alcohol components function as a stabilizer. These fatty acid alcohol components function as a stabilizer. These fatty acid alcohol components are derived from the reduction of a long-chain saturated fatty acid containing at least- 14 carbon atoms.
  • compositions comprising a mast cell stabilizer or a HIF prolyl hydroxylase domain inhibitor, or a combination thereof can be administered by aerosol.
  • aerosol for example, this can be accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing a composition comprising a mast cell stabilizer or a HIF prolyl hydroxylase domain inhibitor preparation.
  • a nonaqueous (e.g., fluorocarbon propellant) suspension could be used.
  • Sonic nebulizers can also be used.
  • An aqueous aerosol is made by formulating an aqueous solution or suspension of the agent together with conventional pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary with the requirements of the particular compound.
  • mast stabilizers and/or HIF prolyl hydroxylase domain inhibitors for the manufacture of a medicament
  • Another aspect of this disclosure is directed to a use of a mast cell stabilizer for the manufacture of a medicament for use in the treatment of pulmonary hypertension.
  • Another aspect of this disclosure is directed to a use of a HIF prolyl hydroxylase domain inhibitor for the manufacture of a medicament for use in the treatment of pulmonary hypertension.
  • Another aspect of this disclosure is directed to a use of a mast cell stabilizer and a HIF prolyl hydroxylase domain inhibitor for the manufacture of a medicament for use in the treatment of pulmonary hypertension.
  • the mast cell stabilizer is selected from the group consisting of cromoglicic acid, ketotifen, olopatadine, rupatadine, mepolizumab, omalizumab, pemirolast, quercetin, nedocromil, azelastine, tranilast,
  • the mast cell stabilizer is nedocromil.
  • the mast cell stabilizer is administered systemically.
  • the mast cell stabilizer is administered locally to the lung.
  • the HIF prolyl hydroxylase domain inhibitor is selected from the group consisting of Roxadustat (RXD) (FG-4592), Vadadustat (AKB- 6548), Daprodustat (GSK- 1278863), and Molidustat (BAY 85-3934).
  • the HIF prolyl hydroxylase domain inhibitor is Roxadustat (RXD) (FG-4592).
  • the HIF prolyl hydroxylase domain inhibitor is administered systemically. In some embodiments, the HIF prolyl hydroxylase domain inhibitor is administered locally to the lung.
  • the pulmonary hypertension is pulmonary arterial hypertension (PAH).
  • PAH pulmonary arterial hypertension
  • Rat model - PAH chemically induced with monocrotaline (MCT) and 2.
  • the inventors demonstrate in these murine models of PAH that mast cells, part of the inflammatory response, play a crucial role in PAH and therapeutically targeting their activity diminishes severity of the disease.
  • Rat model - PAH chemically induced with monocrotaline (MCT) (FIGS. 1 - 7).
  • MCT monocrotaline
  • CON vehicle
  • the mast cell stabilizer nedocromil was administered by pellet implanted subcutaneously (s.c.), prior to the MCT-injection and for the duration of the experiment.
  • Neonatal CD1 mice were continuously exposed to 80% oxygen for 2 weeks followed by return to room air for an additional 3 weeks (High Oxygen, HO). Controls were age matched (5 weeks) in room air (RA or control). The HIF stabilizer roxadustat (RXD) was administered during exposure to hyperoxia as previously reported (Hoppe G. et ah, PNAS, 2016, 113: E2516-2525). Tissues were analyzed at the 5-week time point.
  • FIGS. 2A-2C To determine whether mast cells contribute to remodeling and thickening of the PA associated with PAH as in the MCT-injected rats, rats were treated with the mast cell stabilizer, nedocromil (FIG. 2C). Microdissected PAs from control, MCT-injected, and MCT-injected treated with nedocromil were fixed, sectioned and analyzed for wall thickness and collagen. Representative cross-sections of size-matched PAs stained for collagen with Gomori trichrome are shown in FIGS. 2A-2C.
  • PA from control (CON) rat had minimal collagen staining in the wall measuring (60 mm) (FIG. 2A).
  • PA from MCT-rat was significantly different and remodeled with a wall thickness measuring 150 mm and plenty of collagen (FIG. 2B).
  • the PA from MCT rat treated with the mast cell stabilizer nedocromil had minimal collagen staining and remodeling with a wall thickness of 40 mm (FIG. 2C).
  • FIG. 4A - 4C compares the echocardiographic recordings of
  • the MCT-rats exhibit wave reflection (white arrows), typical of PAH (FIG. 4B) which is absent in MCT-rats + mast cell stabilizer (FIG. 4C) and control (CON) rats (FIG. 4A).
  • FIGS. 5 A - 5D show representative consecutive sections of RV from MCT-injected (FIG. 5B, FIG. 5D) and control (FIG. 5A, FIG. 5C) rats, stained for mast cells (FIG. 5A and FIG. 5B) and collagen (FIG. 5C and FIG. 5D).
  • FIGS. 5A - 5D show representative consecutive sections of RV from MCT-injected (FIG. 5B, FIG. 5D) and control (FIG. 5A, FIG. 5C) rats, stained for mast cells (FIG. 5A and FIG. 5B) and collagen (FIG. 5C and FIG. 5D).
  • the MCT -injected rat also has abundant collagen as shown by the blue staining seen in FIG. 5D whereas there was minimal collagen staining in control rat (FIG. 5C).
  • the spatial distribution of mast cells correlated with the collagen stained region of the RV in the MCT-injected rat.
  • FIGS. 6A - 6C compares representative rat echocardiograms from control (CON) (FIG. 6A), MCT-injected (FIG. 6B) and MCT- injected treated with nedecromil (FIG. 6C). The typical sign of right ventricular overload were observed in the MCT-injected rat (FIG. 6B), namely a flattening of the
  • interventricular septum Dshaped left ventricle
  • MCT-injected rats treated with nedocromil, the mast cell stabilizer, prevented RVH as shown by the donut- shaped left ventricle (FIG. 6C) that was similar to CON (FIG. 6A).
  • Vasoconstriction is a key feature of PAH.
  • vascular smooth muscle expresses Angiotensin II receptor, type 1 (ATiR) which when activated causes vasoconstriction.
  • AZA Angiotensin II receptor
  • mast cell renin (5, 6) and the ensuing ANG II lead to vasoconstriction of the PA was tested.
  • Mast cell-dependent isometric constriction was measured by myograph in isolated rings of PA excised from ⁇ MCT-injected rats (PAH). Individual PA rings are first exposed to high extracellular K + (60 mM) to induce a constriction response.
  • mast cell-dependent constrictions are then measured in response to chemically-induced mast cell degranulation using compound 48/80 (C48/80) (300 J,l9/ml).
  • FIGS. 1A - 7 show that mast cells and their products make a significant contribution to MGT-induced PAH. Inhibiting mast cell activity in vivo with a mast cell stabilizer (nedocromil) or inhibiting the ANG II ATiR ex vivo in pulmonary artery rings, attenuates PAH.
  • a mast cell stabilizer nedocromil
  • ANG II ATiR ex vivo in pulmonary artery rings

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Abstract

La présente invention concerne des méthodes de traitement de l'hypertension pulmonaire consistant à administrer à un sujet qui a besoin d'un tel traitement une quantité efficace d'un stabilisateur de mastocytes, ou une quantité efficace d'un inhibiteur de domaine de HIF-prolyl-hydroxylase, ou une quantité efficace d'une association d'un stabilisateur de mastocytes et d'un inhibiteur de domaine de HIF-prolyl-hydroxylase.
PCT/US2019/049943 2018-09-10 2019-09-06 Méthodes de traitement de l'hypertension pulmonaire Ceased WO2020055687A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114028569A (zh) * 2021-12-20 2022-02-11 中国医学科学院基础医学研究所 免疫球蛋白IgE在诊断和/或治疗高血压中的用途
US12357628B2 (en) 2018-01-09 2025-07-15 Cornell University Prevention and treatment of organ fibrosis

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160346246A1 (en) * 2014-02-10 2016-12-01 Patara Pharma, LLC Methods for the treatment of lung diseases with mast cell stabilizers
WO2017191114A1 (fr) * 2016-05-03 2017-11-09 Bayer Aktiengesellschaft Dérivés d'hétéroaryltriazole substitués par hydroxyalkyle et utilisations associées

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160346246A1 (en) * 2014-02-10 2016-12-01 Patara Pharma, LLC Methods for the treatment of lung diseases with mast cell stabilizers
WO2017191114A1 (fr) * 2016-05-03 2017-11-09 Bayer Aktiengesellschaft Dérivés d'hétéroaryltriazole substitués par hydroxyalkyle et utilisations associées

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12357628B2 (en) 2018-01-09 2025-07-15 Cornell University Prevention and treatment of organ fibrosis
CN114028569A (zh) * 2021-12-20 2022-02-11 中国医学科学院基础医学研究所 免疫球蛋白IgE在诊断和/或治疗高血压中的用途

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