Methods and compositions for prevention and treatment of cardiac hypertrophy

Abstract

Methods are provided of treating cardiac hypertrophy in a mammalian subject comprising administering to the subject an anti-hypertrophic effective amount of an ion channel TR-PV1 inhibitor. The methods include treatment of a symptom of cardiac hypertrophy in the subject comprises cardiac remodeling, cardiac fibrosis, apoptosis, hypertension, or heart failure

1 - 12 . (canceled) 
     
     
         13 . A method of treating arrhythmias, kidney dysfunction, hypertension, or heart failure in a mammalian subject comprising administering to the subject an effective amount of an ion channel TRPV1 inhibitor. 
     
     
         14 . The method according to  claim 13 , comprising treating arrhymthmias. 
     
     
         15 . The method according to  claim 13 , comprising treating kidney dysfunction. 
     
     
         16 . The method according to  claim 13 , comprising treating hypertension. 
     
     
         17 . The method according to  claim 13  wherein the inhibitor is selected from the group consisting of:
 N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)-tetrahydropyrazine-1(2H)-carboxamide; 
 N-(3-Methoxyphenyl)-4-chlorocinnamide; 
 1-Isoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)-urea; 
 (2E)-N-(2,3-Dihydro-1,4-benzodioxin-6-yl)-3-[4-(1,1-dimethylethyl)phenyl]-2-propenamide; 
 2-Acetylamino-4-[6′-(4-trifluoromethylphenyl)-pyrimidin-4′-yl-oxy]-benzothiazole; 
 N-(2-bromophenyl-N′-[((R)-1-(5-trifluoromethyl-2-pyridyl)pyrrolidin-3-yl)]urea; 
 N-(2-bromophenyl)-N′-{2-[ethyl(3-methylphenyl)amino]ethyl}urea; 
 (R)-(5-tert -butyl-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-4-yl)-urea; 
 N-(Isoquinolin-5-yl)-N′-[spiro-(cyclobutane-1,2′-(3′,4′-dihydro-benzopyran-4′-yl))]urea; 
 (2R)-4-(3-chloro-2-pyridinyl)-2-methyl-N-[4-(trifluoromethyl)phenyl]-1-piperazinecarboxamide; 
 4-(4′-Trifluoromethyl-anilino)-7-(3′-trifluoromethyl-pyridin-2-yl)-quinazoline; 
 N-[2-(4-chlorophenyl)ethyl]-1,3,4,5-tetrahydro-7,8-dihydroxy-2H-2-benzazepine-2-carbothioamide; 
 (5R*,8R*,6E,9E)-5,8-Dimethyl-4-methylenetetradeca-6,9-dienoic acid; 
 1-(3-Fluorobenzyl)-2-(N-(1,2-dimethyl-1,3-isoindazol-5-yl)-acetamido)-{pyridine-[3,4-b]-pyrrole}; 
 N-(4-chlorobenzyl)-N′-(1-methyl-1H-indazol-4-yl)urea; 
 N-(4-tert-butylbenzyl)-N′-(1-methyl-1H-indazol-4-yl)urea; 
 N-(3-fluoro-4-(trifluoromethyl)benzyl)-N′-(1-methyl-1H-indazol-4-yl)-urea; 
 N-(4-fluoro-3-(trifluoromethyl)benzyl)-N′-(1-methyl-1H-indazol-4-yl)-urea; 
 N-(3 ,4-dichlorobenzyl)-N′-(1-methyl-1H-indazol-4-yl)urea; 
 N-(2,4-dichlorobenzyl)-N′-(1-methyl-1H-indazol-4-yl)urea; 
 N-(4-ethylbenzyl)-N′-(1-methyl-1H-indazol-4-yl)urea; 
 N-(2-chlorobenzyl)-N′-(1-methyl-1H-indazol-4-yl)urea; 
 N-(4-fluorobenzyl)-N′-(1-methyl-1H-indazol-4-yl)urea; 
 N-(2-fluorobenzyl)-N′-(1-methyl-1H-indazol-4-yl)urea; 
 N-[1-(bromophenyl)ethyl-N′-(1-methyl-1H-Indazol-4-yl)urea; 
 N-(1-methyl-1H-indazol-4-yl)-N′-{4-[(trifluoromethyl)thio]benzyl}urea; 
 1-(2,3-dichlorophenyl)-3-[2-(N-ethyl-3-methylanilino)ethyl]urea; 
 1-[2-(N-ethyl-3-methylanilino)ethyl]-3-naphthalen-1-ylurea; 
 1-(4-bromophenyl)-3-[2-(N-ethyl-3-methylanilino)ethyl]urea; 
 1-(3-bromophenyl)-3-[2-(N-ethyl-3-methylanilino)ethyl]urea; 
 1-(chlorophenyl)-3-[2-(N-ethyl-3-methylanilino)ethyl]urea; 
 1-[2-(N-ethyl-3-methylanilino)ethyl]-3-(2-fluorophenyl)urea; 
 1-[2-1 N-ethyl-3-methylanilino)ethyl]-3-(2-methylphenyl)urea; 
 1-[2-(N-ethyl-3-methylanilino)ethyl]-3-phenylurea; 
 2-[(2-bromophenyl)carbamoylamino]ethyl-ethylmethyl-(3-methylphenyl)azanium iodide; 
 1-(2-bromophenyl)-3-[2-(N-ethyl-3-fluoro-4-methylanilino)ethyl]urea; 
 1-(2-bromophenyl)-3-[2-(N-ethyl-3,4-difluoroanilino)ethyl]urea; 
 1-(2-bromophenyl)-3-[2-(N-ethyl-3-fluoroanilino)ethyl]urea; 
 1-(2-bromophenyl)-3-[2-(N-ethyl-4-methylanilino)ethyl]urea; 
 1-(2-bromophenyl)-3-[2-(N-ethyl-2-methylanilino)ethyl]urea; 
 1-(2-bromophenyl)-3-[2-(N-ethylanilino)ethyl]urea; 
 N-[2-[(2-bromophenyl)carbamoylamino]ethyl]-N-(3-methylphenyl)acetamide; 
 1-[2-{N-benzyl-3-methylanilino)ethyl]-3-(2-bromophenyl)urea; 
 1-(2-bromophenyl)-3-[2-(2,3-dimethylanilino)ethyl]urea; 
 1-(2-bromophenyl)-3-[2-(3-methylaniIino)ethyl]urea; 
 1-(2,5-dichlorophenyl)-3-[2-(N-ethyl-3-methylanilino)ethyl]urea; 
 4-fluoro-4-(3-methylpyridin-2-yl)-N-[4-trifluoromethylphenyl]piperidine-1-carboxamide; 
 4-fluoro-4(pyridin-2-yl)N-[4-trifluoromethylphenyl]piperidine-1-carboxamide; 
 4-fluoro-4(pyridine-2-yl)N-[4-trifluoromethylbenzyl]piperidine-1-carboxamide; 
 2-{4-fluoro-1-[4-trifluoromethylbenzoyl]piperidin-4-yl}pyridine; 
 2-(4-fluoro-1-{[4-trifluoromethylphenyl]acetyl }piperidin-4-yl)pyridine; 
 2-(4-fluoro-1-{3-[4-trifluoromethylphenyl]propanoyl}piperidin-4-yl)pyridine; 
 4-fluoro-4-(1-methyl-1H-imidazol-2-yl)-N-[4-trifluoromethylphenyl]piperidine-1-carboxamide; 
 4-methoxy-4-pyridin-2-yl-N-[4-trifluoromethylphenyl]piperidine-1-carboxamide; 
 4-methoxy-4-pyridin-2-yl-N-[4-trifluoromethylbenzyl]piperidine-1-carboxamide; 
 4-fluoro-N-(4-isopropylphenyl)-4-(3-methylpyridin-2-yl)piperidine-1-carboxamide; 
 4-fluoro-4-(3-methylpyridin-2-yl)-N-{4-[ 1,2,2,2-tetrafluoro-1-trifluoromethylethyl]phenyl}piperidine-1-carboxamide; 
 N-(4-Tert-butylphenyl)-4-fluoro-4-(3-methylpyridin-2-yl)piperidine-1-carboxamide; 
 4-fluoro-4-(3-methylpyridin-2-yl)-N-[4-(pentafluoro-lambda(sup 6)-sulfanyl)phenyl]piperidine-1-carboxamide; 
 N-(4-Butylphenyl)-4-fluoro-4-(3-methylpyridin-2-yl)piperidine-1-carboxamide; 
 N-(4-Benzylphenyl)-4-fluoro-4-(3-methylpyridin-2-yl)piperidine-1-carboxamide; 
 N-biphenyl-4-yl-4-fluoro-4-(3-methylpyridin-2-yl)piperidine-1-carboxamide; 
 4-fluoro-4-(3-methylpyridin-2-yl)-N-[5-trifluoromethylpyridin-2-yl]piperidine-1-carboxamide; 
 4-(3-chloropyridin-2-yl)-4-fluoro-N-[4-trifluoromethylphenyl]piperidine-1-carboxamide; 
 4-fluoro-4-(3-fluoropyridin-2-yl)-N-[4-trifluoromethylphenyl]piperidine-1-carboxamide; 
 4-fluoro-4-(3-methoxypyridin-2-yl)-N-[4-trifluoromethylphenyl]piperidine-1-carboxamide; 
 4-fluoro-4-(3-methylpyridin-2-yl)-N-[4-trifluoromethylphenyl]piperidine-1-carbothioamide; 
 N′-cyano-4-fluoro-4-(3-methylpyridin-2-yl)-N-[4-trifluoromethylphenyl]piperidine-1-carboximidamide; 
 4-fluoro-4-(3-methylpyridin-2-yl)-N′-(1-phenylpiperidin-4-yl)-N-[4-trifluoromethylphenyl]piperidine-1-carboximidamide; 
 4-fluoro-4-phenyl-N-[4-trifluoromethylphenyl]piperidine-1-carboxamide; 
 (+/−)-(syn)-4-fluoro-2-methyl-4-(3-methylpyridin-2-yl)-N-[4-trifluoromethylphenyl]piperidine-1-carboxamide; 
 4-(fluoromethyl)-4-pyridin-2-yl-N-[4-trifluoromethylphenyl]piperidine-1-carboxamide; 
 syn- and anti-3-fluoro-3-pyridin-2-yl-N-[4-trifluoromethylphenyl]-8-azabicyclo[3.2-.1]octane-8-carboxamide; 
 3-fluoro-3-pyridin-2-yl-N-[4-trifluoromethylphenyl]-8-azabicyclo[3.2.1]octane-8-carboxamide; 
 4-fluoro-4-pyrimidin-2-yl-N-[4-trifluoromethylphenyl]piperidine-1-carboxamide; 
 4-fluoro-4-(3-phenylpropyl)-N-[4-trifluoromethylphenyl]piperidine-1-carboxamide; 
 2-[4-fluoro-4-(3-methylpyridin-2-yl)piperidin-1-yl]-6-trifluoromethyl-1H-benzimidazole; 
 2-(4-fluoro-4-pyridin-2-yl)piperidin-1-yl)-6-(trifluoromethyl)-1H-benzimidazole; 
 4-fluoro-N-[4trifluoromethylphenyl]-4-[3-trifluoromethylpyridin-2-yl]piperidine-1-carboxamide; 
 4-fluoro-N-(4-methylphenyl)-4-(3-methylpyridin-2-yl)piperidine-1-carboxamide; 
 N-(4-ethylphenyl)-4-fluoro-4-(3-methylpyridin-2-yl)piperidine-1-carboxamide; 
 N-(4-chlorophenyl)-4-fluoro-4-(3-methylpyridin-2-yl)piperidine-1-carboxamide; 
 4-fluoro-4-(3-methylpyridin-2-yl)-N-[4-trifluoromethoxyphenyl]piperidine-1-carboxamide; 
 N-(4-cyanophenyl)-4-fluoro-4-(3-methylpyridin-2-yl)piperidine-1-carboxamide; 
 N-[4-dimethylaminophenyl]-4-fluoro-4-(3-methylpyridin-2-yl)piperidine-1-carboxamide; 
 1-(2-(3,3-dimethylbutyl)-4-(trifluoromethyl)benzyl)-3-(1-methyl-1H-indazo-1-4-yl)urea; 
 N-acetyl-1-phenylalanyl-1-leucinamide; 
 and pharmaceutically acceptable salts thereof. 
 
     
     
         18 . The method according to  claim 14  wherein the inhibitor is selected from the group consisting of:
 N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)-tetrahydropyrazine-1(2H)-carboxamide; 
 N-(3-Methoxyphenyl)-4-chlorocinnamide; 
 1-lsoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)-urea; 
 (2E)-N-(2,3-Dihydro-1,4-benzodioxin-6-yl)-3-[4-(1,1-dimethylethyl)phenyl]-2-propenamide; 
 2-Acetylamino-4-[6′-(4-trifluoromethylphenyl)-pyrimidin-4′-yl-oxy]-benzothiazole; 
 N-(2-bromophenyl-N′-[((R)-1-(5-trifluoromethyl-2-pyridyl)pyrrolidin-3-yl)]urea; 
 N-(2-bromophenyl)-N′-{2-[ethyl(3-methylphenyl)amino]ethyl}urea; 
 (R)-(5-tert -butyl-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-4-yl)-urea; 
 N-(Isoquinolin-5-yl)-N′-[spiro-(cyclobutane-1,2′-(3′,4′-dihydro-benzopyran-4′-yl))]urea; 
 (2R)-4-(3-chloro-2-pyridinyl)-2-methyl-N-[4-(trifluoromethyl)phenyl]-1-piperazinecarboxamide; 
 4-(4′-Trifluoromethyl-anilino)-7-(3′-trifluoromethyl-pyridin-2-yl)-quinazoline; 
 N-[2-(4-chlorophenyl)ethyl]-1,3,4,5-tetrahydro-7,8-dihydroxy-2H-2-benzazepine-2-carbothioamide; 
 (5R*,8R*,6E,9E)-5,8-Dimethyl-4-methylenetetradeca-6,9-dienoic acid; 
 1-(3-Fluorobenzyl)-2-(N-(1,2-dimethyl-1,3-isoindazol-5-yl)-acetamido)-{pyrdine-[3,4-b]-pyrrole}; 
 N-(4-chlorobenzyl)-N′-(1-methyl-1H-indazol-4-yl)urea; 
 N-(4-tert-butylbenzyl)-N′-(1-methyl-1H-indazol-4-yl)urea; 
 N-(3-fluoro-4-(trifluoromethyl)benzyl)-N′-(1-methyl-1H-indazol-4-yl)-urea; 
 N-(4-fluoro-3-(trifluoromethyl)benzyl)-N′-(1-methyl-1H-indazol-4-yl)-urea; 
 N-(3,4-dichlorobenzyl)-N′-(1-methyl-1H-indazol-4-yl)urea; 
 N-(2,4-dichlorobenzyl)-N′-(1-methyl-1H-indazol-4-yl)urea; 
 N-(4-ethylbenzyl)-N′-(1-methyl-1H-indazol-4-yl)urea; 
 N-(2-chlorobenzyl)-N′-(1-methyl-1H-indazol-4-yl)urea; 
 N-(4-fluorobenzyl)-N′-(1-methyl-1H-indazol-4-yl)urea; 
 N-(2-fluorobenzyl)-N′-(1-methyl-1H-indazol-4-yl)urea; 
 N-[1-(bromophenyl)ethyl-N′-(1-methyl-1H-Indazol-4-yl)urea; 
 N-(1-methyl-1H-indazol-4-yl)-N′-{4-[(trifluoromethyl)thio]benzyl}urea; 
 1-(2,3-dichlorophenyl)-3-[2-(N-ethyl-3-methylanilino)ethyl]urea; 
 1-[2-(N-ethyl-3-methylanilino)ethyl]-3-naphthalen-1-ylurea; 
 1-(4-bromophenyl)-3-[2-(N-ethyl-3-methylanilino)ethyl]urea; 
 1-(3-bromophenyl)-3-[2-(N-ethyl-3-methylanilino)ethyl]urea; 
 1-(chlorophenyl)-3-[2-(N-ethyl-3-methylanilino)ethyl]urea; 
 1-[2-(N-ethyl-3-methylanilino)ethyl]-3-(2-fluorophenyl)urea; 
 1-[2-{N-ethyl-3-methylanilino)ethyl]-3-(2-methylphenyl)urea; 
 1-[2-(N-ethyl-3-methylanilino)ethyl]-3-phenylurea; 
 2-[(2-bromophenyl)carbamoylamino]ethyl-ethylmethyl-(3-methylphenyl)azanium iodide; 
 1-(2-bromophenyl)-3-[2-(N-ethyl-3-fluoro-4-methylanilino)ethyl]urea; 
 1-(2-bromophenyl)-3-[2-(N-ethyl-3,4-difluoroanilino)ethyl]urea; 
 1-(2-bromophenyl)-3-[2-(N-ethyl-3-fluoroanilino)ethyl]urea; 
 1-(2-bromophenyl)-3-[2-(N-ethyl-4-methylanilino)ethyl]urea; 
 1-(2-bromophenyl)-3-[2-(N-ethyl-2-methylanilino)ethyl]urea; 
 1-(2-bromophenyl)-3-[2-(N-ethylanilino)ethyl]urea; 
 N-[2-[(2-bromophenyl)carbamoylamino]ethyl]-N-(3-methylphenyl)acetamide; 
 1-[2-1N-benzyl-3-methylanilino)ethyl]-3-(2-bromophenyl)urea; 
 1-(2-bromophenyl)-3-[2-(2,3-dimethylanilino)ethyl]urea; 
 1-(2-bromophenyl)-3-[2-(3-methylaniIino)ethyl]urea; 
 1-(2,5-dichlorophenyl)-3-[2-(N-ethyl-3-methylanilino)ethyl]urea; 
 4-fluoro-4-(3-methylpyridin-2-yl)-N-[4-trifluoromethylphenyl]piperidine-1-carboxamide; 
 4-fluoro-4(pyridin-2-yl)N-[4-trifluoromethylphenyl]piperidine-1-carboxamide; 
 4-fluoro-4(pyridine-2-yl)N-[4-trifluoromethylbenzyl]piperidine-1-carboxamide; 
 2-{4-fluoro-1-[4-trifluoromethylbenzoyl]piperidin-4-yl}pyridine; 
 2-(4-fluoro-1-{[4-trifluoromethylphenyl]acetyl}piperidin-4-yl)pyridine; 
 2-(4-fluoro-1-{3-[4-trifluoromethylphenyl]propanoyl}piperidin-4-yl)pyridine; 
 4-fluoro-4-(1-methyl-1H-imidazol-2-yl)-N-[4-trifluoromethylphenyl]piperidine-1-carboxamide; 
 4-methoxy-4-pyridin-2-yl-N-[4-trifluoromethylphenyl]piperidine-1-carboxamide; 
 4-methoxy-4-pyridin-2-yl-N-[4-trifluoromethylbenzyl]piperidine-1-carboxamide; 
 4-fluoro-N-(4-isopropylphenyl)-4-(3-methylpyridin-2-yl)piperidine-1-carboxamide; 
 4-fluoro-4-(3-methylpyridin-2-yl)-N-{4-[1,2,2,2-tetrafluoro-1-trifluoromethylethyl]phenyl}piperidine-1-carboxamide; 
 N-(4-Tert-butylphenyl)-4-fluoro-4-(3-methylpyridin-2-yl)piperidine-1-carboxamide; 
 4-fluoro-4-(3-methylpyridin-2-yl)-N-[4-(pentafluoro-lambda(sup 6)-sulfanyl)phenyl]piperidine-1-carboxamide; 
 N-(4-Butylphenyl)-4-fluoro-4-(3-methylpyridin-2-yl)piperidine-1-carboxamide; 
 N-(4-Benzylphenyl)-4-fluoro-4-(3-methylpyridin-2-yl)piperidine-1-carboxamide ; 
 N-biphenyl-4-yl-4-fluoro-4-(3-methylpyridin-2-yl)piperidine-1-carboxamide ; 
 4-fluoro-4-(3-methylpyridin-2-yl)-N-[5-trifluoromethylpyridin-2-yl]piperidine-1-carboxamide; 
 4-(3-chloropyridin-2-yl)-4-fluoro-N-[4-trifluoromethylphenyl]piperidine-1-carboxamide; 
 4-fluoro-4-(3-fluoropyridin-2-yl)-N-[4-trifluoromethylphenyl]piperidine-1-carboxamide; 
 4-fluoro-4-(3-methoxypyridin-2-yl)-N-[4-trifluoromethylphenyl]piperidine-1-carboxamide; 
 4-fluoro-4-(3-methylpyridin-2-yl)-N-[4-trifluoromethylphenyl]piperidine-1-carbothioamide; 
 N′-cyano-4-fluoro-4-(3-methylpyridin-2-yl)-N-[4-trifluoromethylphenyl]piperidine-1-carboximidamide; 
 4-fluoro-4-(3-methylpyridin-2-yl)-N′-(1-phenylpiperidin-4-yl)-N-[4-trifluoromethylphenyl]piperidine-1-carboximidamide; 
 4-fluoro-4-phenyl-N-[4-trifluoromethylphenyl]piperidine-1-carboxamide; 
 (+/−)-(syn)-4-fluoro-2-methyl-4-(3-methylpyridin-2-yl)-N-[4-trifluoromethylphenyl]piperidine-1-carboxamide; 
 4-(fluoromethyl)-4-pyridin-2-yl-N-[4-trifluoromethylphenyl]piperidine-1-carboxamide; 
 syn- and anti-3-fluoro-3-pyridin-2-yl-N-[4-trifluoromethylphenyl]-8-azabicyclo[3.2-.1]octane-8-carboxamide; 
 3-fluoro-3-pyridin-2-yl-N-[4-trifluoromethylphenyl]-8-azabicyclo[3.2.1]octane-8-carboxamide; 
 4-fluoro-4-pyrimidin-2-yl-N-[4-trifluoromethylphenyl]piperidine-1-carboxamide; 
 4-fluoro-4-(3-phenylpropyl)-N-[4-trifluoromethylphenyl]piperidine-1-carboxamide; 
 2-[4-fluoro-4-(3-methylpyridin-2-yl)piperidin-1-yl]-6-trifluoromethyl-1H-benzimidazole; 
 2-(4-fluoro-4-pyridin-2-ylpiperidin-1-yl)-6-(trifluoromethyl)-1H-benzimidazole; 
 4-fluoro-N-[4trifluoromethylphenyl]-4-[3-trifluoromethylpyridin-2-yl]piperidine-1-carboxamide; 
 4-fluoro-N-(4-methylphenyl)-4-(3-methylpyridin-2-yl)piperidine-1-carboxamide; 
 N-(4-ethylphenyl)-4-fluoro-4-(3-methylpyridin-2-yl)piperidine-1-carboxamide; 
 N-(4-chlorophenyl)-4-fluoro-4-(3-methylpyridin-2-yl)piperidine-1-carboxamide; 
 4-fluoro-4-(3-methylpyridin-2-yl)-N-[4-trifluoromethoxyphenyl]piperidine-1-carboxamide; 
 N-(4-cyanophenyl)-4-fluoro-4-(3-methylpyridin-2-yl)piperidine-1-carboxamide; 
 N-[4-dimethylaminophenyl]-4-fluoro-4-(3-methylpyridin-2-yl)piperidine-1-carboxamide; 
 1-(2-(3,3-dimethylbutyl)-4-(trifluoromethyl)benzyl)-3-(1-methyl-1H-indazo-1-4-yl)urea; 
 N-acetyl-1-phenylalanyl-1-leucinamide; 
 and pharmaceutically acceptable salts thereof. 
 
     
     
         19 . The method according to  claim 13  wherein the inhibitor comprises N-(4-t-butyl-phenyl)-4-(3-chloropyridin-2-yl)-tetrahydropyrazine-1(2H)-carboxamide or a pharmaceutically acceptable salt thereof. 
     
     
         20 . The method according to  claim 14  wherein the inhibitor comprises N-(4-t-butyl-phenyl)-4-(3-chloropyridin-2-yl)-tetrahydropyrazine-1(2H)-carboxamide or a pharmaceutically acceptable salt thereof. 
     
     
         21 . The method according to  claim 16  wherein the inhibitor comprises N-(4-t-butyl-phenyl)-4-(3-chloropyridin-2-yl)-tetrahydropyrazine-1(2H)-carboxamide or a pharmaceutically acceptable salt thereof.