Bridgehead modification of trihalocycloheptabenzopyridine lead to a potent farnesyl protein transferase inhibitor with improved oral metabolic stability

Modification of the ethano bridge of the core structure of the antitumor agent, SARASAR® (SCH66336) with concomitant introduction of a sulfonamide moiety off the distal piperidine afforded inhibitor 9-(S-), a compound with greatly improved PK profile. Other compounds with enhanced FPTase inhibitory activity were obtained as exemplified by amide 10-(S-) and urea 11-(S-): these compounds demonstrated activity in picomolar range.