Nonpeptide insulin receptor agonists

Abstract

Modulation of the activity of the insulin receptor, enhancement of glucose uptake by cells, and other effects significant in the control and management of diabetes are accomplished using compounds of the formula wherein each A is independently a proton-accepting substituent; each R is independently a noninterfering substituent; n is 0, 1, or 2; and each linker is independently an isostere of —NHCONH— or of —N═N— or of —NHCO—. Compounds in the genus of Formula (1) can also be used for structure activity studies to identify features responsible for the relevant activities.

1. A method to modulate the kinase activity of insulin receptor which method comprises contacting said insulin receptor or the kinase portion thereof with a compound of the formula 
                   
       wherein
 each A is independently a proton-accepting substituent;  
 each R is independently a noninterfering substituent;  
 each n is independently 0, 1, or 2; and  
 each linker is independently an isostere of —NHCOHN— or of —N═N— or of —NHCO—;  
 said compound provided in an amount effective to modulate said kinase activity.  
 
     
     
       2. The method of  claim 1  wherein each A is independently —SO 3 X or —COOX wherein X is H or a cation. 
     
     
       3. The method of  claim 1  wherein each R is independently OH or 
                   wherein linker is as defined above.    
     
     
       4. The method of  claim 1  wherein n is 0 or 1 and each R is independently OH. 
     
     
       5. The method of  claim 1  wherein said compound is of a formula selected from the group consisting of 
                   
       wherein
 each linker is independently either —N═N— or —NHCO—.  
 
     
     
       6. A method to potentiate the insulin activation of insulin receptor which method comprises contacting said insulin receptor or the kinase portion thereof with insulin and with a compound of the formula 
                   
       wherein
 each A is independently a proton-accepting substituent;  
 each R is independently a noninterfering substituent;  
 n is 0, 1, or 2; and  
 each linker is independently an isostere of —NHCONH— or of —N═N— or of —NHCO—;  
 said compound provided in an amount effective to potentiate said insulin activation.  
 
     
     
       7. The method of  claim 6  wherein each A is independently —SO 3 X or —COOX wherein X is H or a cation. 
     
     
       8. The method of  claim 6  wherein each R is independently OH or 
                   
       
        
       
     
     
       9. The method of  claim 6  wherein n is 0 or 1 and each R is independently OH. 
     
     
       10. The method of  claim 6  wherein said compound is of a formula selected from the group consisting of 
                   
       wherein
 each linker is independently either —N═N— or —NHCO—.  
 
     
     
       11. A method to potentiate the stimulation by insulin of cellular glucose uptake which method comprises contacting cells displaying the insulin receptor with insulin and with a compound of the formula 
                   
       wherein
 each A is independently a proton-accepting substituent;  
 each R is independently a noninterfering substituent;  
 n is 0, 1, or 2; and  
 each linker is independently an isostere of —NHCONH— or of —N═N— or of —NHCO—;  
 said compound provided in an amount effective to potentiate said glucose uptake.  
 
     
     
       12. The method of  claim 11  wherein each A is independently —SO 3 X or —COOX wherein X is H or a cation. 
     
     
       13. The method of  claim 11  wherein each R is independently OH or 
                   
       
        
       
     
     
       14. The method of  claim 11  wherein n is 0 or 1 and each R is independently OH. 
     
     
       15. The method of  claim 11  wherein said compound is of a formula selected from the group consisting of 
                   
       wherein
 each linker is independently either —N═N— or —NHCO—.  
 
     
     
       16. A method to stimulate the uptake of glucose in cells displaying the insulin receptor which method comprises contacting said cells with a compound of the formula 
                   
       wherein
 each A is independently a proton-accepting substituent;  
 each R is independently a noninterfering substituent;  
 n is 0, 1, or 2; and  
 each linker is independently an isostere of —NHCONH— or of —N═N— or of —NHCO—;  
 said compound provided in an amount effective to stimulate glucose uptake.  
 
     
     
       17. The method of  claim 16  wherein each A is independently —SO 3 X or —COOX wherein X is H or a cation. 
     
     
       18. The method of  claim 16  wherein each R is independently OH or 
                   
       
        
       
     
     
       19. The method of  claim 16  wherein n is 0 or 1 and each R is independently OH. 
     
     
       20. The method of  claim 16  wherein said compound is of a formula selected from the group consisting of 
                   
       wherein
 each linker is independently either —N═N— or —NHCO—.  
 
     
     
       21. A method to lower blood glucose in a diabetic subject which method comprises administering to said subject a compound of the formula 
                   
       wherein
 each A is independently a proton-accepting substituent;  
 each R is independently a noninterfering substituent;  
 n is 0, 1, or 2; and  
 each linker is independently an isostere of —NHCONH— or of —N═N— or of —NHCO—;  
 said compound provided in an amount effective to lower blood glucose.  
 
     
     
       22. The method of  claim 21  wherein each A is independently —SO 3 X or —COOX wherein X is H or a cation. 
     
     
       23. The method of  claim 21  wherein each R is independently OH or 
                   
       
        
       
     
     
       24. The method of  claim 21  wherein n is 0 or 1 and each R is independently OH. 
     
     
       25. The method of  claim 21  wherein said compound is of a formula selected from the group consisting of 
                   
       wherein
 each linker is independently either —N═N— or —NHCO—.  
 
     
     
       26. A compound of the formula: 
                   
       
        
       
     
     
       27. A method to lower blood glucose in a diabetic subject comprising administering to the subject a blood glucose- lowering effective amount of the compound of    claim 26   .   
     
     
       28. A pharmaceutical composition comprising the compound of  claim 26  and a pharmaceutically acceptable excipient.