Treatment of post-angioplasty restenosis and atherosclerosis with Ras antagonists
View Patent ↗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 treating a mammal suffering from or at risk of vascular injury, comprising: administering to a patient a Ras antagonist in an mount effective to treat the mammal, 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.
2. The method of claim 1 wherein the Ras antagonist is farnesyl-thiosalicyclic acid (FTS).
3. The method of claim 1 wherein the Ras antagonist is 2-chloro-5-farnesylaminobenzoic acid (NFCB).
4. The method of claim 1 wherein the Ras antagonist is farnesyl thionicotinic acid (FTN).
5. The method of claim 1 wherein the Ras antagonist is 5-fluoro-FTS.
6. The method of claim 1 wherein the Ras antagonist is 5-chloro-FTS.
7. The method of claim 1 wherein the Ras antagonist is 4-chloro-FTS.
8. The method of claim 1 wherein the Ras antagonist is S-farnesyl-thiosalicylic acid methyl ester.
9. The method of claim 1 wherein the Ras antagonist is administered parenterally.
10. The method of claim 1 wherein the Ras antagonist is administered orally.
11. The method of claim 1 wherein the Ras antagonist is administered prophylactically.
12. The method of claim 1 wherein the Ras antagonist is administered in a formulation containing a cyclodextrin.
13. The method of claim 1 wherein the Ras is activated Ras.
14. The method of claim 1 wherein the vascular injury is post-angioplasty restenosis.
15. The method of claim 14 wherein the Ras antagonist is administered prophylactically.
16. The method of claim 1 wherein the vascular injury is atherosclerosis.
17. 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;
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, akenyl, aminoalkyl, nitroalkyl, nitro, halo, amino, mono- or di-alkylamino, mercapto, mercaptoalkyl, axido, or thiocyanato; and
X represents O, S, SO, SO 2 , NH or Se.
18. 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 ;
R 2 represents 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; and
X represents O, S, SO, SO 2 , NH or Se.
19. The method of claim 2 , wherein the vascular injury is atherosclerosis.
20. The method of claim 2 , wherein the vascular injury is post-angioplasty restenosis.
21. The method of claim 2 , wherein the Ras antagonist is administered prophylactically.
22. The method of claim 2 , 19 or 20 wherein the Ras antagonist is administered orally.
23. The method of claim 5 , wherein the vascular injury is atherosclerosis.
24. The method of claim 5 , wherein the vascular injury is post-angioplasty restenosis.
25. The method of claim 5 , wherein the Ras antagonist is administered prophylactically.
26. The method of claim 5 , 23 or 24 wherein the Ras antagonist is administered orally.
27. The method of claim 6 , wherein the vascular injury is atherosclerosis.
28. The method of claim 6 , wherein the vascular injury is post-angioplasty restenosis.
29. The method of claim 6 , wherein the Ras antagonist is administered prophylactically.
30. The method of claim 6 , 27 or 28 wherein the Ras antagonist is administered orally.
31. The method of claim 7 , wherein the vascular injury is atherosclerosis.
32. The method of claim 7 , wherein the vascular injury is post-angioplasty restenosis.
33. The method of claim 7 , wherein the Ras antagonist is administered prophylactically.
34. The method of claim 7 , 31 or 32 wherein the Ras antagonist is administered orally.
35. The method of claim 8 , wherein the vascular injury is atherosclerosis.
36. The method of claim 8 , wherein the vascular injury is post-angioplasty restenosis.
37. The method of claim 8 , wherein the Ras antagonist is administered prophylactically.
38. The method of claim 8 , 35 , or 36 wherein the Ras antagonist is administered orally.
39. The method of any one of claims 1 - 16 , wherein the mammal is a human.
40. The method of any one of claims 17 - 21 , wherein the mammal is human.
41. The method of claim 22 , wherein the mammal is a human.
42. The method of any one of claims 23 - 25 , wherein the mammal is a human.
43. The method of claim 26 , wherein he mammal is a human.
44. The method of any one of claims 27 - 29 , wherein the mammal is a human.
45. The method of claim 30 , wherein he mammal is a human.
46. The method of any one of claims 31 - 33 , wherein the mammal is a human.
47. The method of claim 34 , wherein he mammal is a human.
48. The method of any one of claims 35 - 37 , wherein the mammal is a human.
49. The method of claim 38 , wherein the mammal is a human.