-PIPERIDINYL]-2-OXO-ETHYL]-1-PIPERIDINECARBOXAMIDE (SCH-66336) - A VERY POTENT FARNESYL-PROTEIN TRANSFERASE INHIBITOR AS A NOVEL ANTITUMOR AGENT())

We have previously shown that appropriate modification of the benzocyc loheptapyridine tricyclic ring system can provide potent farnesyl prot ein transferase (FPT) inhibitors with good cellular activity. Our labo ratories have also established that incorporation of either pyridinyla cetyl N-oxide or 4-N-carboxamidopiperidinylacetyl moieties results in pharmacokinetically stable inhibitors that are orally efficacious in n ude mice. We now demonstrate that further elaboration of the tricyclic ring system by introducing a bromine atom at the 7- or the 10-positio n of the 3-bromo-8-chlorotricyclic ring system provides compounds that have superior potency and selectivity in FPT inhibition. These compou nds have good serum levels and half-lives when given orally to rodents and primates. In vitro and in vivo evaluation of a panel of these inh ibitors has led to identification of 15 (SCH 66336) as a highly potent (IC50 = 1.9 nM) antitumor agent that is currently undergoing human cl inical trials.