Compositions and treatments for inhibiting kinase and/or hmg-coa reductase

Abstract

The present invention provides compositions of matter, kits and methods for their use in the treatment of MAP kinase-related conditions and/or HMG-CoA reductase-related conditions. In particular, the invention provides compositions for treating inflammatory and/or cardiovascular conditions in an animal subject by inhibiting p38α MAP kinase and/or HMG-CoA reductase, as well as providing formulations and modes of administering such compositions. The invention further provides methods for the rational design of inhibitors of MAP kinase, HMG-COA reductase, or both for use in the practice of the present invention.

1 . A method of inhibiting a MAP kinase comprising administering an effective amount of at least one compound comprising formula VII  
     
       
         
         
             
             
         
       
       wherein R 1  is  
       n being 0 or any integer;  
       R 2  is optionally substituted alkyl, aryl, or heteroaryl;  
       R 3  is any substituent;  
       R 4  is optionally substituted  
       
         
           
           
               
               
           
         
       
       and R 5  is optionally substituted aryl or heteroaryl, or a salt thereof.  
     
   
   
       2 . The method as recited in  claim 1  wherein said R 1  has the following stereochemistry:  
     
       
         
         
             
             
         
       
     
   
   
       3 . The method as recited in  claim 1  wherein said inhibited MAP kinase is p38 MAP kinase.  
   
   
       4 . The method as recited in  claim 1 , further comprising inhibiting an HMG CoA reductase.  
   
   
       5 . The method as recited in  claim 1  wherein said administering treats a MAP kinase-related condition.  
   
   
       6 . The method as recited in  claim 1  wherein said administering treats a MAP kinase-related condition and an HMG CoA reductase-related condition.  
   
   
       7 . The method as recited in  claim 1  wherein said administering treats an inflammatory condition.  
   
   
       8 . A compound comprising formula VII:  
     
       
         
         
             
             
         
       
       wherein R 1  is  
       
         
           
           
               
               
           
         
       
       n being 0 or any integer;  
       R 2  is optionally substituted alkyl, aryl, or heteroaryl;  
       R 3  is any substituent;  
       R 4  is optionally substituted  
       
         
           
           
               
               
           
         
       
       optionally substituted  
       
         
           
           
               
               
           
         
       
       or substituted  
       
         
           
           
               
               
           
         
       
       and R 5  is optionally substituted aryl or heteroaryl, or a salt thereof.  
     
   
   
       9 . The compound as recited in  claim 8  wherein R 2  is a C 3-4  branched alkyl group.  
   
   
       10 . The compound as recited in  claim 8  wherein R 2  is isopropyl.  
   
   
       11 . The compound as recited in  claim 8  wherein R 4  is  
     
       
         
         
             
             
         
       
     
   
   
       12 . The compound as recited in  claim 8  wherein R 4  is  
     
       
         
         
             
             
         
       
     
   
   
       13 . The compound as recited in  claim 8  wherein R 4  is  
     
       
         
         
             
             
         
       
     
   
   
       14 . The compound as recited in  claim 8  wherein R 4  is  
     
       
         
         
             
             
         
       
     
   
   
       15 . The compound as recited in  claim 8  wherein R 4  is  
     
       
         
         
             
             
         
       
     
   
   
       16 . The compound as recited in  claim 8  wherein R 4  is  
     
       
         
         
             
             
         
       
     
   
   
       17 . The compound as recited in  claim 8  wherein R 4  is  
     
       
         
         
             
             
         
       
     
   
   
       18 . The compound as recited in  claim 8  wherein R 5  is an optionally substituted phenyl group.  
   
   
       19 . The compound as recited in  claim 8  wherein R 5  is 4-fluorophenyl.  
   
   
       20 . The compound as recited in  claim 8  wherein R5 is 3-trifluoromethylphenyl.  
   
   
       21 . The compound as recited in  claim 8  wherein R 3  is —CONH— aryl.  
   
   
       22 . The compound as recited in  claim 8  wherein R 3  is —CONH-phenyl.  
   
   
       23 - 26 . (canceled)  
   
   
       27 . A compound comprising formula VII:  
     
       
         
         
             
             
         
       
       wherein R 1  is  
       
         
           
           
               
               
           
         
       
       n being 0 or any integer;  
       R 2  is optionally substituted alkyl, aryl, or heteroaryl;  
       R 3  is any substituent;  
       R 4  is substituted  
       
         
           
           
               
               
           
         
       
       wherein said R 4  is substituted with one or more optionally substituted amino groups or optionally substituted alkoxy groups;  
       and R 5  is optionally substituted aryl or heteroaryl, or a salt thereof.  
     
   
   
       28 . A compound comprising formula VIIa:  
     
       
         
         
             
             
         
       
       wherein R 1  is  
       
         
           
           
               
               
           
         
       
       n being 0 or any integer;  
       R 2  is optionally substituted alkyl, aryl, or heteroaryl;  
       the pyridinyl ring is substituted;  
       and R 5  is optionally substituted aryl or heteroaryl, or a salt thereof.  
     
   
   
       29 . A compound comprising formula VIb:  
     
       
         
         
             
             
         
       
       wherein R 1  is  
       
         
           
           
               
               
           
         
       
       n being 0 or any integer;  
       R 2  is optionally substituted alkyl, aryl, or heteroaryl;  
       the pyrimidinyl ring is optionally substituted;  
       and R 5  is optionally substituted aryl or heteroaryl, or a salt thereof.  
     
   
   
       30 . A pharmaceutical composition comprising an effective amount of at least one compound as recited in  claim 8  with a pharmaceutically acceptable carrier.  
   
   
       31 . A method of treating a condition in a subject in need thereof comprising administering to said subject an effective amount of at least one compound comprising formula VII:  
     
       
         
         
             
             
         
       
       wherein R 1  is  
       n being 0 or any integer;  
       R 2  is optionally substituted alkyl, aryl, or heteroaryl;  
       R 3  is any substituent;  
       R 4  is optionally substituted  
       
         
           
           
               
               
           
         
       
       optionally substituted  
       
         
           
           
               
               
           
         
       
       or substituted  
       
         
           
           
               
               
           
         
       
       and R 5  is optionally substituted aryl or heteroaryl, or a salt thereof.  
     
   
   
       32 . The method as recited in  claim 31  wherein said condition is a MAP kinase and/or an HMG-CoA reductase-related condition.