Treatment of post-angioplasty restenosis and atherosclerosis with ras antagonists

Abstract

Disclosed are methods for inhibiting Ras activity such as cell proliferation associated with vascular injury such as post-angioplasty restenosis and atherosclerosis. Preferred Ras antagonists are S-trans-trans farnesylthiosalicylic acid (FTS) and structurally related compounds (or analogs) thereof.

1 . A method of inhibiting Ras activity in a mammal suffering from or at risk of vascular injury, comprising: administering to a patient a Ras antagonist in an amount effective to inhibit the activity.  
     
     
         2 . The method of  claim 1  wherein the Ras antagonist is represented by the formula  
       
         
           
           
               
               
           
         
         wherein  
         R 1  represents farnesyl, geranyl or geranyl-geranyl;  
         Z represents C—R 6  or N;  
         R 2  represents H, CN, the groups COOR 7 , SO 3 R 7 , CONR 7 R 8 , COOM, SO 3 M and SO 2 NR 7 R 8 , wherein R 7  and R 8  are each independently hydrogen, alkyl or alkenyl, and wherein M is a cation; R 3 , R 4 , R 5  and R 6  are each independently hydrogen, carboxyl, alkyl, alkenyl, aminoalkyl, nitroalkyl, nitro, halo, amino, mono- or di-alkylamino, mercapto, mercaptoalkyl, axido, or thiocyanato;  
         X represents O, S, SO, SO 2 , NH or Se; and the quaternary ammonium salts and N-oxides of the compounds of said formula when Z is N.  
       
     
     
         3 . The method of  claim 1  wherein the Ras antagonist is farnesyl-thiosalicyclic acid (FTS).  
     
     
         4 . The method of  claim 1  wherein the Ras antagonist is 2-chloro-5-farnesylaminobenzoic acid (NFCB).  
     
     
         5 . The method of  claim 1  wherein the Ras antagonist is farnesyl thionicoatinic acid (FTN).  
     
     
         6 . The method of  claim 1  wherein the Ras antagonist is 5-fluoro-FTS.  
     
     
         7 . The method of  claim 1  wherein the Ras antagonist is 5-chloro-FTS.  
     
     
         8 . The method of  claim 1  wherein the Ras antagonist is 4-chloro-FTS.  
     
     
         9 . The method of  claim 1  wherein the Ras antagonist is S-farnesyl-methylthiosalicylic acid.  
     
     
         10 . The method of  claim 1  wherein the Ras antagonist is administered parenterally.  
     
     
         11 . The method of  claim 1  wherein the Ras antagonist is administered orally.  
     
     
         12 . The method of  claim 1  wherein the Ras antagonist is administered prophylactically.  
     
     
         13 . The method of  claim 1  wherein the Ras antagonist is administered in a formulation containing a cyclodextrin.  
     
     
         14 . The method of  claim 14  wherein the Ras is activated Ras.  
     
     
         15 . The method of  claim 1  wherein the vascular injury is post-angioplasty restenosis.  
     
     
         16 . The method of  claim 15  wherein the Ras antagonist is administered prophylactically.  
     
     
         17 . The method of  claim 1  wherein the vascular injury is atherosclerosis.  
     
     
         18 . A method of displacing Ras from its cell membrane anchor in a mammal suffering from or at risk of vascular injury, comprising administering to the mammal a Ras antagonist in an amount effective to effect said displacing, wherein the Ras antagonist is represented by the formula  
       
         
           
           
               
               
           
         
         wherein  
         R 1  represents farnesyl, geranyl or geranyl-geranyl;  
         Z represents C-R 6  or N;  
         R 2  represents H, CN, the groups COOR 7 , SO 3 R 7 , CONR 7 R 8 , COOM, SO 3 M and SO 2 NR 7 R 8 , wherein R 7  and R 8  are each independently hydrogen, alkyl or alkenyl, and wherein M is a cation; R 3 , R 4 , R 5  and R 6  are each independently hydrogen, carboxyl, alkyl, alkenyl, aminoalkyl, nitroalkyl, nitro, halo, amino, mono- or di-alkylamino, mercapto, mercaptoalkyl, axido, or thiocyanato;  
         X represents O, S, SO, SO 2 , NH or Se; and the quaternary ammonium salts and N-oxides of the compounds of said formula when Z is N.  
       
     
     
         19 . The method of  claim 18  wherein said Ras antagonist is farnesyl-thiosalicyclic acid (FTS).