Chemical modulators of store-operated calcium channels and their therapeutic applications

Abstract

Methods of identification of inhibitors of calcium release-activated calcium (CRAC) channel and small molecule inhibitors of CRAC channel, including methods of their synthesis and pharmaceutical use, are disclosed.

1 . A method of treatment of a disease, disorder, or condition treatable by inhibiting CRAC channel in a subject, comprising administering to a subject in need thereof an amount of a CRAC channel inhibitor effective to inhibit CRAC channel, wherein the CRAC channel inhibitor is a compound of Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, or a hydrate thereof, wherein 
         X is an optionally substituted C6-C10 aryl or an optionally substituted C5-C10 heteroaryl; 
         Y is an optionally substituted C1-C8 alkyl, an optionally substituted C6-C10 aryl-C1-C8 alkyl, an optionally substituted C5-C10 heteroaryl-C1-C8 alkyl, an optionally substituted C3-C10 heteroalkyl, an optionally substituted C3-C6 heterocyclyl, an optionally substituted C6-C10 aryl, or an optionally substituted C5-C10 heteroaryl; and 
         Z is an optionally substituted C6-C10 aryl or an optionally substituted C5-C10 heteroaryl. 
       
     
     
         2 . The method of  claim 1 , wherein X is an optionally substituted phenyl. 
     
     
         3 . The method of  claim 1 , wherein X is a phenyl substituted with one, two, or three groups selected from C1-C6 alkyl, carboxyl, alkoxycarbonyl, and amido group. 
     
     
         4 . The method of  claim 1 , wherein the compound has the structure of Formula II: 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is H, an optionally substituted C1-C6 alkyl, COOH, COOR 2 , CONH 2 , or CONHR 2 ; 
         R 2  is an optionally substituted C1-C6 alkyl; 
         Y is an optionally substituted C1-C8 alkyl, an optionally substituted C6-C10 aryl-C1-C8 alkyl, or an optionally substituted C5-C10 heteroaryl-C1-C8 alkyl; and 
         Z is an optionally substituted C6-C10 aryl or an optionally substituted C5-C10 heteroaryl. 
       
     
     
         5 . The method of  claim 1 , wherein Y is an optionally substituted phenethyl. 
     
     
         6 . The method of  claim 1 , wherein the compound has the structure of Formula III: 
       
         
           
           
               
               
           
         
         wherein 
         R1 is H, COOH, COOR 2 , or CONHR 2 ; 
         R 2  is an optionally substituted C1-C6 alkyl; 
         R 4  is H or an optionally substituted C1-C6 alkyl; 
         R 5  is H or an optionally substituted C1-C6 alkyl; and 
         Z is an optionally substituted C6-C10 aryl or an optionally substituted C5-C10 heteroaryl. 
       
     
     
         7 . The method of  claim 1 , wherein Y is methyl, ethyl, propyl, n-butyl, tert-butyl, cyclopropyl, phenyl, benzyl, 4-methoxybenzyl, 3,4-dimethoxyphenyl, 4-sulfonamidophenethyl, or 5-methylbenzo[d][1,3]dioxolyl. 
     
     
         8 . The method of  claim 1 , wherein Z is phenyl, 4-halophenyl, 3-trifluoromethyl-phenyl, 2,5-dichlorophenyl, 3-chloro-4-methyl-phenyl, 2-methoxy-phenyl, 4-methoxycarbonyl-phenyl, benzo[d][1,3]dioxolyl, 3,5-dichlorophenyl, 3-methoxyphenyl, or 3-halophenyl. 
     
     
         9 . The method of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         10 . The method of  claim 1 , wherein the condition is an immune system disease, a hyperplastic disease, or cancer. 
     
     
         11 . The method of  claim 1 , wherein the condition is colon cancer, breast cancer, leukemia, or glioma. 
     
     
         12 . The method of  claim 1 , wherein the condition is an organ or a tissue transplant rejection. 
     
     
         13 . A compound represented by Formula II: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, or a hydrate thereof, wherein 
         R 1  is selected from H, C1-C6 alkyl, COOH, COOR 2 , or CONHR 2 , and 
         R 2  is an optionally substituted C1-C6 alkyl; 
         Y is an optionally substituted C1-C8 alkyl, an optionally substituted C6-C10 aryl-C1-C8 alkyl, or an optionally substituted C5-C10 heteroaryl-C1-C8 alkyl; and 
         Z is an optionally substituted C6-C10 aryl or an optionally substituted C5-C10 heteroaryl. 
       
     
     
         14 . The compound of  claim 13 , wherein Y is an optionally substituted phenethyl. 
     
     
         15 . The compound of  claim 13 , wherein Y is 4-sulfonamidophenethyl. 
     
     
         16 . The compound of  claim 13 , wherein the compound has the structure of Formula III: 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is H, an optionally substituted C1-C6 alkyl, COOH, COOR 2 , CONH 2 , or CONHR 2 ; 
         R 2  is an optionally substituted C1-C6 alkyl; 
         R 4  is H or an optionally substituted C1-C6 alkyl; 
         R 5  is H or an optionally substituted C1-C6 alkyl; and 
         Z is an optionally substituted C6-C10 aryl or an optionally substituted C5-C10 heteroaryl. 
       
     
     
         17 . The compound of  claim 13 , wherein Y is methyl, ethyl, propyl, n-butyl, tert-butyl, cyclopropyl, phenyl, benzyl, 4-methoxybenzyl, 3,4-dimethoxyphenyl, 4-sulfonamidophenethyl, or 5-methylbenzo[d][1,3]dioxolyl. 
     
     
         18 . The compound of  claim 13 , wherein Z is phenyl, 4-halophenyl, 3-trifluoromethyl-phenyl, 2,5-dichlorophenyl, 3-chloro-4-methyl-phenyl, 2-methoxy-phenyl, 4-methoxycarbonyl-phenyl, benzo[d][1,3]dioxolyl, 3,5-dichlorophenyl, 3-methoxyphenyl, or 3-halophenyl. 
     
     
         19 . The compound of  claim 13 , wherein the compound is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         20 . A pharmaceutical composition comprising the compound of  claim 13  and a pharmaceutically acceptable carrier.