Trpc ion channel inhibitors for use in therapy

Abstract

Described herein are inhibitors Transient Receptor Potential Canonical (TRPC) ion channels comprising TRPC4 protein and/or TRPC5 protein for use in combating obesity and other medical conditions including insulin resistance associated with Type II diabetes or development of Type II diabetes (pre-diabetes), metabolic syndrome, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). Also disclosed is the use of the inhibitors for cosmetic purposes, such as cosmetic weight loss.

1 . An inhibitor which directly targets a Transient Receptor Potential Canonical (TRPC) ion channel comprising TRPC4 and/or TRPC5 as present in adipocytes for use in the treatment or prophylaxis of a condition selected from obesity, insulin resistance, metabolic syndrome, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). 
     
     
         2 . An inhibitor as claimed in  claim 1 , wherein the TRPC ion channel comprises TRPC5. 
     
     
         3 . An inhibitor as claimed in  claim 1 , wherein the TRPC ion channel comprises TRPC4. 
     
     
         4 . An inhibitor as claimed in  claim 1 , wherein the TRPC ion channel further comprises TRPC1. 
     
     
         5 . An inhibitor as claimed in  claim 1  which directly inhibits the expression or function of TRPC4 and/or TRPC5 
     
     
         6 . An inhibitor as claimed in  claim 1 , wherein said inhibitor is for use in the treatment or prophylaxis of obesity. 
     
     
         7 . An inhibitor as claimed in  claim 1  for use in the treatment or prophylaxis of insulin resistance in a subject. 
     
     
         8 . An inhibitor as claimed in  claim 7 , wherein the subject is obese. 
     
     
         9 . An inhibitor as claimed in  claim 7  wherein the insulin resistance is associated with Type II diabetes or prediabetes. 
     
     
         10 . An inhibitor as claimed in  claim 1  for use in the treatment or prophylaxis of metabolic syndrome. 
     
     
         11 . An inhibitor as claimed in  claim 10 , wherein the treatment of metabolic syndrome comprises reducing abdominal obesity and/or reducing fasting blood glucose concentration. 
     
     
         12 . An inhibitor as claimed in  claim 1  wherein the inhibitor is administered to a subject predetermined to have an elevated level in adipose tissue relative to control of one or more screening targets selected from TRPC1 mRNA and/or protein, TRPC4 mRNA and/or protein and TRPC5 mRNA and/or protein. 
     
     
         13 . A method of identifying a subject according to  claim 12 , which comprises:
 a. determining the level of one or more screening targets selected from TRPC1 protein and/or mRNA, TRPC4 mRNA and/or protein and or TRPC5 mRNA and/or protein in a sample of adipose tissue from a subject; and   b. selecting said subject for administration of the inhibitor if the level of said screening target exceeds a control level.   
     
     
         14 . An inhibitor as claimed in  claim 1 , wherein the inhibitor is an antibody or an antigen-binding fragment thereof. 
     
     
         15 . An inhibitor as claimed in  claim 14  wherein said antibody binds TRPC4 and/or TRPC5. 
     
     
         16 . An inhibitor as claimed in  claim 1  wherein the inhibitor is a siRNA or antisense oligonucleotide. 
     
     
         17 . An inhibitor as claimed in  claim 16  which inhibits expression of TRPC4 protein, TRPC5 protein or both, 
     
     
         18 . An inhibitor as claimed in  claim 1 , wherein the inhibitor is a small molecule of 2000 daltons or less. 
     
     
         19 . The inhibitor of  claim 18 , wherein the inhibitor is a compound of the Formula (II), or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is C 1-6  alkyl, C 2-6  alkenyl or C 2-6  alkynyl, each of which is optionally substituted with 1-4 R 5 ; 
 R 2  is C 1-6  alkyl, C 1-6  heteroalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  haloalkyl, halo, C 1-6  haloalkoxy, hydroxyl, C 1-6  alkoxy, C 3-7  cycloalkyloxy, C 6-10  aryl, C 6-10  aryloxy, C 7-16  arylalkoxy, amino, C 1-6  akylamino, C 2-12  dialkylamino, —S(O) x R′ (wherein x is 0, 1 or 2 and each R′ is independently H or C 1-6  alkyl), heterocycloalkyl, heteroaryl, heteroaryloxy, sulfonamidyl, amido, urea, sulfonylurea, acyl, nitro, cyano, 
 wherein each C 1-6  alkyl, C 1-6  heteroalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  haloalkyl, C 1-6 haloalkoxy, hydroxyl, C 1-6  alkoxy, C 3-7  cycloalkyloxy, C 6-10  aryl, C 6-10  aryloxy, C 7-16  arylalkoxy, amino, C 1-6  akylamino, C 2-12  dialkylamino, —S(O) x R′, heterocycloalkyl, heteroaryl, heteroaryloxy, sulfonamidyl, amido, urea, sulfonylurea, acyl, is optionally substituted with 1-3 R 6 ; 
 R 3  is C 1-6  alkyl, C 1-6  heteroalkyl, C 3-7  cycloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 2-6  hydroxyalkyl, or C 1-6  alkoxy, each of which is optionally substituted with 1-4 R 7 ; 
 R 4  is C1.6 alkyl, C1.6 heteroalkyl, C 2-6  alkenyl or C 2-6  alkynyl, each of which is optionally substituted with 1-4 R 1 ; 
 R 5 , R 6 , R 7 , and R 8  are each independently hydrogen, C 1-6  alkyl, C 1-6  heteroalkyl, halo, C 1-6  haloalkyl, C 1-6  haloalkoxy, hydroxyl, C 1-6  alkoxy, amino, C 1-6  alkylamino, C 2-12  dialkylamino, cyano, nitro, amido, C 1-6  alkylamido, C 2-12  dialkylamido, —S(O) x R′ (wherein x is 0, 1 or 2), —C(O)OR′, —C(O)R′, C 3-7  cycloalkyl, C 6-10  aryl, heterocycloalkyl, or heteroaryl, wherein each R′ is independently H or C 1-6  alkyl, 
 wherein each of C 1-6  alkyl, C 1-6  heteroalkyl, C 1-6  haloalkyl, C 1-6  haloalkoxy, hydroxyl, C 1-6  alkoxy, amino, C 1-6  alkylamino, C 2-12  dialkylamino, amido, C 1-6  alkylamido, C 2-12  dialkylamido, —C(O)O—C 1-6  alkyl, C 3-7  cycloalkyl, C 6-10  aryl, heterocycloalkyl, or heteroaryl is optionally substituted with 1-3 R 9 ; and 
 each R 9  is independently C 1-6  alkyl, C 1-6  heteroalkyl, C 1-6  haloalkyl, C 1-6  haloalkoxy, heterocycloalkyl, C 6-10  aryl, heteroaryl, C 4-10  cycloalkylalkyl, heterocycloalkyl-C 1-6  alkyl, C 7-16  arylalkyl, heteroaryl-C 1-6  alkyl, halo, hydroxyl, C 1-6  alkoxy, C 6-10  aryloxy, C 7-16  arylalkoxy, C2-s alkoxyalkoxy, amino, C 1-6  akylamino, C 2-12  dialkylamino, C 1-6  aryl-amino-C 1-6  alkyl, C 1-6  alkyl-amino-C 2-12  dialkyl, —S(O) x R′ (wherein x is 0, 1 or 2), sulfonamidyl, amido, urea, sulfonylurea, acyl, —C(O)—C 1-6  alkyl, —C(O)—C 6-10  aryl, —NHC(O)—C 1-4  alkyl, —NHC(O)—C 6-10  aryl, —C(O)NR′R′, —C(O)NH—C 6-10  aryl, —C(O)OR′, —OC(O)R′, acyl, nitro, or cyano. 
 
     
     
         20 . The inhibitor of  claim 19 , wherein the inhibitor is: 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salt thereof. 
       
     
     
         21 . The inhibitor of  claim 19 , wherein the inhibitor is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         22 . The inhibitor of  claim 18 , wherein the inhibitor is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         23 . A compound of the formula (X), or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are independently H or C 1-4  alkyl. 
       
     
     
         24 . A compound of  claim 23  of the formula (Xa): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         25 .- 28 . (canceled)