INHIBITORS OF FARNESYL-PROTEIN TRANSFERASE

摘要

The present invention comprises analogs of the CA<1>A<2>X motif of the protein Ras that is modified by farnesylation in vivo. These CA<1>A<2>X analogs inhibit the farnesyl-protein transferase and the farnesylation of certain proteins. Furthermore, these CA<1>A<2>X analogs differ from those previously described as inhibitors of farnesyl-protein transferase in that they do not have a thiol moiety. The lack of the thiol offers unique advantages in terms of improved pharmacokinetic behavior in animals, prevention of thiol-dependent chemical reactions, such as rapid autoxidation and disulfide formation with endogenous thiols, and reduced systemic toxicity. The compounds of the instant invention also incorporate a cyclic amine moiety in the A<2> position of the motif. Further contained in this invention are chemotherapeutic compositions containing these farnesyl transferase inhibitors and methods for their production.