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; m is 0 or 1; n is 0, 1, or 2; and each linker is independently an isostere 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;  
         m is 0 or 1;  
         n is 0, 1, or 2; and  
         each linker is independently an isostere 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 the formula  
       
         
           
           
               
               
           
         
         wherein each linker is independently either —NHCO— or —CH═CH—.  
       
     
     
         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;  
         m is 0 or 1;  
         n is 0, 1, or 2; and  
         each linker is independently an isostere 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 the formula  
       
         
           
           
               
               
           
         
         wherein each linker is independently either —NHCO— or —CH═CH—.  
       
     
     
         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;  
         m is 0 or 1;  
         n is 0, 1, or 2,and  
         each linker is independently an isostere 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 the formula  
       
         
           
           
               
               
           
         
         wherein each linker is independently either —NHCO— or —CH═CH—.  
       
     
     
         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;  
         m is 0 or 1,  
         n is 0, 1 or 2; and  
         each linker is independently an isostere 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 the formula  
       
         
           
           
               
               
           
         
         wherein each linker is independently either —NHCO— or —CH═CH—.  
       
     
     
         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;  
         m is 0 or 1;  
         n is 0, 1, or 2; and  
         each linker is independently an isostere 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 the formula  
       
         
           
           
               
               
           
         
         wherein each linker is independently either —NHCO— or —CH═CH—.  
       
     
     
         26 . A method to identify a compound that activates a receptor containing a kinase portion by autophosphorylation, which method comprises 
 contacting each member of a set of maximally diverse candidate compounds with said receptor or kinase portion thereof;    detecting the amount of phosphotyrosine on the receptor or kinase portion contacted with each set member; and    identifying as a successful candidate at least one member of the set wherein phosphotyrosine is detected in increased amount in the receptor or kinase with which it was contacted.    
     
     
         27 . The method of  claim 26  wherein said detecting of tyrosine phosphate comprises contacting said receptor or kinase portion with an antibody immunoreactive with tyrosine kinase; and 
 detecting any complex formed between said antibody and said receptor or kinase portion.  
 
     
     
         28 . The method of  claim 26  wherein said maximally diverse set is obtained by a method which comprises: 
 providing fingerprints for a library of compounds, said fingerprints consisting of the recorded degrees of reactivity of each compound with respect to a reference panel of substances representing a majority of chemical space;  
 arranging the fingerprints into clusters of similar fingerprints;  
 selecting a compound representative of each cluster; and  
 assembling said selected compounds into said set of maximally diverse candidates.  
 
     
     
         29 . A method to design and synthesize a molecule that activates the insulin receptor which method comprises 
 assessing an activator identified by the method of  claim 26  or TER12, TER3938, TER3935, TER16998, TER17003 or other compound shown to activate the kinase activity of the insulin receptor for structural features which correlate with said activities;    synthesizing a compound containing these structural features; and    testing said compound for its ability to activate the insulin receptor to verify it as an activator.    
     
     
         30 . A method to screen candidate compounds for ability to activate the kinase activity insulin receptor, which method comprises 
 obtaining a fingerprint of each candidate with respect to a reference panel;    obtaining a fingerprint of an activator identified by the method of  claim 26  or TER12, TER3938, TER3935, TER16998, TER17003 or other compound shown to activate the kinase activity of the insulin receptor with respect to the same reference panel;    comparing the fingerprint of each candidate with that of any of said activator identified by the method of  claim 26  or TER12, TER3938, TER3935, TER16998, TER17003 or other compound shown to activate the kinase activity of the insulin receptor; and    identifying as the successful candidate a compound whose fingerprint resembles that of an activator identified by the method of  claim 26  or TER12, TER3938, TER3935. TER16998, TER17003 or other compound shown to activate the kinase activity of the insulin receptor.    
     
     
         31 . The method of  claim 30  wherein said reference panel is comprised of proteins.  
     
     
         32 . A method to identify a candidate compound which will activate the insulin receptor which method comprises 
 contacting a sample containing at least the kinase portion of the insulin receptor with an activator identified by the method of  claim 26  in the presence and absence of said candidate;    measuring the binding of said activator in the presence and absence of said candidate; and    identifying as the successful candidate a compound for which the binding of activator is diminished in its presence as compared to its absence.    
     
     
         33 . The method of  claim 32  wherein said binding is measured by the activation of the insulin receptor.  
     
     
         34 . The method of  claim 32  wherein said binding is measured by labeling said receptor with labeled activator.  
     
     
         35 . The method of  claim 34  wherein said label is a radioisotope.  
     
     
         36 . A method to identify a candidate compound which will activate the insulin receptor which method comprises 
 contacting a sample containing at least the kinase portion of the insulin receptor with an activator identified by the method of  claim 29  in the presence and absence of said candidate;    measuring the binding of said activator in the presence and absence of said candidate; and    identifying as the successful candidate a compound for which the binding of activator is diminished in its presence as compared to its absence.    
     
     
         37 . The method of  claim 36  wherein said binding is measured by the activation of the insulin receptor.  
     
     
         38 . The method of  claim 36  wherein said binding is measured by labeling said receptor with labeled activator.  
     
     
         39 . The method of  claim 36  wherein said label is a radioisotope.  
     
     
         40 . A method to identify a candidate compound which will activate the insulin receptor which method comprises 
 contacting a sample containing at least the kinase portion of the insulin receptor with an activator identified by the method of  claim 30  in the presence and absence of said candidate;    measuring the binding of said activator in the presence and absence of said candidate; and    identifying as the successful candidate a compound for which the binding of activator is diminished in its presence as compared to its absence.    
     
     
         41 . The method of claim  40  wherein said binding is measured by the activation of the insulin receptor.  
     
     
         42 . The method of claim  40  wherein said binding is measured by labeling said receptor with labeled activator  
     
     
         43 . The method of claim  40  wherein said label is a radioisotope.