Compositions and methods for inhibiting platelet activation and thrombosis

Abstract

The invention provides methods and compositions for reducing platelet activation, platelet aggregation and thrombosis. The invention further provides compositions and methods for treating or preventing diseases or disorders in which the pathology of the disease or disorder involves one or more of platelet activation, platelet aggregation and thrombus formation. The invention additionally relates to the use of protein palmitoylation inhibitors for the reduction of platelet activation, platelet aggregation and thrombosis, as well as to the use of protein palmitoylation as a target for the identification of inhibitors of platelet activation, platelet aggregation and thrombosis.

1 . A method of reducing platelet activation, platelet aggregation or thrombosis, the method comprising administering an effective amount of a palmitoylation inhibitor, such that platelet activation, platelet aggregation or thrombosis is reduced.  
   
   
       2 . The method of  claim 1  wherein said palmitoylation inhibitor comprises a compound of Structure 1 or a pharmaceutically acceptable salt thereof  
     
       
         
         
             
             
         
       
     
     wherein: 
 R and R 3  are selected from the group consisting of H, linear or branched alkyl, aryl, aralkyl, alkenyl, heteroalkyl, heteroaryl, cycloalkyl, cycloalkenyl and substituted derivatives thereof; and  
 R 1  and R 2  are selected from the group consisting of H, linear or branched alkyl, aralkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy and substituted derivatives thereof, or wherein carbon atoms at R 1  and R 2  are bridged to form a substituted or unsubstituted cycloalkyl or cycloalkenyl ring.  
 
   
   
       3 . The method of  claim 2  wherein said substituted derivatives comprise one or more chemical substituents selected from the group consisting of halogen, NO 2 , NH 2 , CO 2 R 4 , COR 4  and OR 4 , wherein R 4  is H or alkyl.  
   
   
       4 . The method of  claim 2  wherein R 3  comprises a linear alkyl chain comprising 3, 4 or 5 carbons.  
   
   
       5 . The method of  claim 2  wherein said palmitoylation inhibitor comprises a compound having one of the following structures:  
     
       
         
         
             
             
         
       
     
   
   
       6 . The method of  claim 2  wherein said palmitoylation inhibitor comprises a compound having the following structure:  
     
       
         
         
             
             
         
       
     
   
   
       7 . A method of treating or preventing a disease or disorder characterized by platelet activation, platelet aggregation or thrombosis, the method comprising administering to an individual an effective amount of a palmitoylation inhibitor, such that platelet activation, platelet aggregation or thrombosis is reduced.  
   
   
       8 . The method of  claim 7  wherein said palmitoylation inhibitor comprises a compound of Structure 1 or a pharmaceutically acceptable salt thereof:  
     
       
         
         
             
             
         
       
     
     wherein: 
 R and R 3  are selected from the group consisting of H, linear or branched alkyl, aryl, aralkyl, alkenyl, heteroalkyl, heteroaryl, cycloalkyl, cycloalkenyl and substituted derivatives thereof; and  
 R 1  and 1(2 are selected from the group consisting of H, linear or branched alkyl, aralkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy and substituted derivatives thereof, or wherein carbon atoms at R 1  and R 2  are bridged to form a substituted or unsubstituted cycloalkyl or cycloalkenyl ring.  
 
   
   
       9 . The method of  claim 8  wherein said substituted derivatives comprise one or more chemical substituents selected from the group consisting of halogen, NO 2 , NH 2 , CO 2 R 4 , COR 4  and OR 4 , wherein R 4  is H or alkyl.  
   
   
       10 . The method of  claim 8  wherein R 3  comprises a linear alkyl chain comprising 3, 4 or 5 carbons.  
   
   
       11 . The method of  claim 8  wherein said palmitoylation inhibitor comprises a compound having one of the following structures:  
     
       
         
         
             
             
         
       
     
   
   
       12 . The method of  claim 8  wherein said palmitoylation inhibitor comprises a compound having the following structure: