Inhibitors of epoxide hydrolases for the treatment of hypertension

Abstract

The invention provides compounds that inhibit epoxide hydrolase in therapeutic applications for treating hypertension. A preferred class of compounds for practicing the invention have the structure shown by Formula 1 wherein Z is oxygen or sulfur, W is carbon phosphorous or sulfur, X and Y is each independently nitrogen, oxygen, or sulfur, and X can further be carbon, at least one of R 1 -R 4 is hydrogen, R 2 is hydrogen when X is nitrogen but is not present when X is sulfur or oxygen, R 4 is hydrogen when Y is nitrogen but is not present when Y is sulfur or oxygen, R 1 and R 3 is each independently C 1 -C 20 substituted or unsubstituted alkyl, cycloalkyl, aryl, acyl, or heterocyclic.

1 . A method of treating hypertension in a patient, the method comprising administering to the patient a therapeutically effective amount of a nucleic acid which inhibits epoxide hydrolase (EH) gene expression. 
     
     
         2 . A method of  claim 1 , wherein the nucleic acid is complementary to a portion of a human gene encoding EH. 
     
     
         3 . A method of  claim 1 , wherein the nucleic acid is DNA. 
     
     
         4 . A method of  claim 1 , wherein the nucleic acid is RNA. 
     
     
         5 . A method of  claim 1 , wherein the nucleic acid is modified to increase resistance to nucleases. 
     
     
         6 . A method of delivering a reactive functionality to epoxide hydrolase, said method comprising contacting said epoxide hydrolase with a compound selected from the group consisting of Formula I and of Formula II, wherein
 (a) compounds of Formula I have the structure   
       
         
           
           
               
               
           
         
         wherein Z is oxygen or sulfur, W is carbon phosphorous or sulfur, X and Y is each independently nitrogen, oxygen, or sulfur, and X can further be carbon, at least one of R 1 -R 4  is hydrogen, R 2  is hydrogen when X is nitrogen but is not present when X is sulfur or oxygen, R 4  is hydrogen when Y is nitrogen but is not present when Y is sulfur or oxygen, R 1  and R 3  are each independently a substituted or unsubstituted alkyl, haloalkyl, cycloalkyl, aryl, acyl, or heterocyclic, and 
         (b) compounds of Formula II have the structure 
       
       
         
           
           
               
               
           
         
         wherein R is alkyl or aryl, the compound is trans- across the epoxide ring, OX is a carbonyl (═O) or hydroxy group (OH) and R′ is a H, alkyl or aryl group, 
         and further wherein said compound of Formula I or Formula II is derivatized with a reactive functionality. 
       
     
     
         7 . A method of  claim 6 , wherein the reactive functionality is an alkylating agent or a Michael acceptor 
     
     
         8 . A method of  claim 7 , wherein the alkylating agent is a halogen. 
     
     
         9 . A method of  claim 7 , wherein the alkylating agent is an epoxide. 
     
     
         10 . A method of  claim 6 , wherein said compound of Formula I or Formula II is derivatized with a Michael acceptor. 
     
     
         11 . A method of  claim 6 , wherein said compound is a compound of Formula I. 
     
     
         12 . A method of  claim 6 , wherein said compound is a compound of Formula II. 
     
     
         13 . A method of detecting epoxide hydrolase, said method comprising contacting said epoxide hydrolase with a compound selected from the group consisting of Formula I and of Formula II, wherein
 (a) compounds of Formula I have the structure   
       
         
           
           
               
               
           
         
         wherein Z is oxygen or sulfur, W is carbon phosphorous or sulfur, X and Y is each independently nitrogen, oxygen, or sulfur, and X can further be carbon, at least one of R 1 -R 4  is hydrogen, R 2  is hydrogen when X is nitrogen but is not present when X is sulfur or oxygen, R 4  is hydrogen when Y is nitrogen but is not present when Y is sulfur or oxygen, R 1  and R 3  are each independently a substituted or unsubstituted alkyl, haloalkyl, cycloalkyl, aryl, acyl, or heterocyclic, and 
         (b) compounds of Formula II have the structure 
       
       
         
           
           
               
               
           
         
         wherein R is alkyl or aryl, the compound is trans- across the epoxide ring, OX is a carbonyl (═O) or hydroxy group (OH) and R′ is a H, alkyl or aryl group, 
         and further wherein said compound of Formula I or Formula II is derivatized with a fluorescent or affinity label.