Identification of pharmacokinetically stable 3,10-dibromo-8-chlorobenzocycloheptapyridine farnesyl protein transferase inhibitors with potent enzyme and cellular activities

Farnesyl protein transferase (FPT) is a promising target for the developmen t of cancer chemotherapeutics because it is responsible for the farnesylati on of oncogenic p21 Ras proteins which are found in nearly 30% of all human cancers and necessary for cellular development and growth. The recent disc overy and progression to phase II clinical trials of trihalobenzocyclohepta pyridine Sch-66336 as a potent inhibitor of FPT with oral, in vivo efficacy in mice have spawned extensive structure-activity relationship studies (SA R) of this class of compounds. Of the many trihalobenzocycloheptapyridine a nalogues prepared, we have identified several which inhibit FPT and cellula r proliferation at single-digit nanomolar concentrations and which have goo d pharmacokinetic properties in mice.