Treatment of cystic diseases

Abstract

The invention described herein pertains to the treatment of cystic diseases. More particularly, the invention described herein relates to methods for treating cystic disease using one or more lysophosphatidic acid antagonists, TMEM16a inhibitors, and/or peroxisome proliferator-activated receptor modulators.

1 . A method for treating cystic disease in a patient in need of relief, the method comprising the step of administering to the patient (a) a therapeutically effective amount of one or more TMEM16a inhibitors; and (b) a therapeutically effective amount of one or more lysophosphatidic acid antagonists, or a therapeutically effective amount of one or more PPAR gamma agonists, or a combination thereof. 
     
     
         2 . The method of  claim 1  wherein the one or more lysophosphatidic acid antagonists are selected from the group consisting of DGPP, cyclic sulfuric acid analogs of 2-oleoyl LPA, Kil6425, L-NASPA, VPC 12204, VPC 12249, VPC 12249-10t, VPC 12249-10t-13d, VPC 32179, VPC 32183, VPC 12031, Thio-ccPA-18:1, Thio-ccPA-16:0, CHF-ccPA, Palmitoyl α-bromomethylene phosphonate, Palmitoyl α-chloromethylene phosphonate, Palmitoyl α-H2-methylene phosphonate, Palmitoyl α-OH-methylene phosphonate, Oleoyl sn-2-AO-LPA, Palmitoyl sn-2-AO-LPA, Alkoxymethylene-phosphonate-LPA (18:1), Alkoxymethylene-phosphonate-LPA (16:0), FAP-10, FAP-12, SPH, SPP, N-palmitoyl-1-serine, N-palmitoyl-1-tyrosine, 2-Amino-3-oxo-3-(tetradeeylamino) propyl dihydrogen phosphate, 2-(Acetylamino)-3-oxo-3-(tetradecylamino) propyl dihydrogen phosphate, 2-Amino-3-(octadecylamino)-3-oxopropyl dihydrogen phosphate, 1,2-(3-Octadecyloxypropane)-bis(dihydrogen phosphate), 1,2-(3-Docosanoyloxypropane)-bis (dihydrogen phosphate), Phosphoric acid monobutyl ester, Phosphoric acid monooctyl ester, Phosphoric acid monooctadecyl ester, Phosphoric acid monodocosyl ester, Acyl LPG 18:1, DPIEL, LPG 14:0, 2(s)-OMPT, 3-(N-((2-(2-((pyridin-3-ylmethylamino)carbonyl)phenyl)phenyl) carbonyl)-N-(2-(2,5-dimethoxyphenyl-)ethyl)amino)propanoic acid hydrochloride, methyl 3-(14-[4-(1[1-(2-chlorophenyl)ethoxy]carbonyl}amino)-3-methyl-5-isoxazolyl]benzyl}sulfanyl)propanoate, and 4′-1[(3-phenylpropyl) (3,4,5-trimethoxybenzoyl)amino]methyl}-2-biphenylyl)acetic acid, and pharmaceutically acceptable salts of the foregoing. 
     
     
         3 . The method of  claim 1  wherein one of the lysophosphatidic acid antagonists is VPC 32183, or a pharmaceutically acceptable salt thereof. 
     
     
         4 . The method of  claim 1  wherein at least one of the lysophosphatidic acid antagonists interferes with the activity of lysophosphatidic acid at one or more lysophosphatidic acid receptors selected from the group consisting of LPA 1 , LPA 2 , LPA 3 , LPA 4 , and LPA 5 . 
     
     
         5 . The method of  claim 1  wherein one of the TMEM16a inhibitors is tannic acid or a pharmaceutically acceptable salt thereof, or a prodrug of any of the foregoing. 
     
     
         6 . The method of  claim 1  wherein the cystic disease is associated at least in part with one or more of polycystic kidney disease, Bardt Biedl syndrome, nephronophthisis, Meckel Gruber syndrome, or oral-facial-digital syndrome. 
     
     
         7 . The method of  claim 1  wherein the cyst resides in an internal organ. 
     
     
         8 . The method of  claim 7  wherein the internal organ is selected from the group consisting of kidney, liver, and pancreas. 
     
     
         9 . The method of  claim 1  wherein the lysophosphatidic acid antagonist is administered orally, parenterally, or by injection. 
     
     
         10 . The method of  claim 9  wherein the lysophosphatidic acid antagonist is administered by injection. 
     
     
         11 . The method of  claim 10  wherein the injection is intravenous. 
     
     
         12 . The method of  claim 10  wherein the injection is intrahepatic. 
     
     
         13 . The method of  claim 10  wherein the injection is intrarenal. 
     
     
         14 . The method of  claim 10  wherein the injection is intrapancreatic. 
     
     
         15 . The method of  claim 10  wherein the injection is a direct infusion. 
     
     
         16 . The method of  claim 1  wherein the lysophosphatidic acid antagonist is administered via an implanted device. 
     
     
         17 . The method of  claim 1  wherein one of the lysophosphatidic acid antagonists is VPC 51299. 
     
     
         18 . The method of  claim 1  wherein the one or more lysophosphatidic acid antagonists are selected from the group consisting of DGPP, cyclic sulfuric acid analogs of 2-oleoyl LPA, Kil6425, VPC 12204, VPC 12249, VPC 12249-10t, VPC 12249-10t-13d, VPC 32179, VPC 32183, VPC 12031, Thio-ccPA-18:1, Thio-ccPA-16:0, CHF-ccPA, Alkoxymethylene-phosphonate-LPA (18:1), Alkoxymethylene-phosphonate-LPA (16:0), FAP-10, FAP-12, SPH, SPP, N-palmitoyl-1-serine, N-palmitoyl-1-tyrosine, 2-Amino-3-oxo-3-(tetradeeylamino) propyl dihydrogen phosphate, 2-(Acetylamino)-3-oxo-3-(tetradecylamino) propyl dihydrogen phosphate, 2-Amino-3-(octadecylamino)-3-oxopropyl dihydrogen phosphate, 1,2-(3-Octadecyloxypropane)-bis(dihydrogen phosphate), 1,2-(3-Docosanoyloxypropane)-bis(dihydrogen phosphate), Phosphoric acid monobutyl ester, Phosphoric acid monooctyl ester, Phosphoric acid monooctadecyl ester, Phosphoric acid monodocosyl ester, Acyl LPG 18:1, DPIEL, LPG 14:0, 2(s)-OMPT, 3-(N-((2-(2-((pyridin-3-ylmethylamino)carbonyl)phenyl)phenyl)carbonyl)-N-(2-(2,5-dimethoxyphenyl-) ethyl)amino)propanoic acid hydrochloride, methyl 3-(14-[4-(1[1-(2-chlorophenyl)ethoxy]carbonyl}amino)-3-methyl-5-isoxazolyl]benzyl}sulfanyl)propanoate, and 4′-1[(3-phenylpropyl)(3,4,5-trimethoxybenzoyl)amino]methyl}-2-biphenylyl)acetic acid, and VPC 51299, and pharmaceutically acceptable salts of the foregoing. 
     
     
         19 . The method of  claim 18  wherein the lysophosphatidic acid is DGPP, or a pharmaceutically acceptable salt thereof.