POTENT, SELECTIVE, AND ORALLY BIOAVAILABLE TRICYCLIC PYRIDYL ACETAMIDE N-OXIDE INHIBITORS OF FARNESYL-PROTEIN TRANSFERASE WITH ENHANCED IN-VIVO ANTITUMOR-ACTIVITY

We previously reported compound 1 as a potent farnesyl protein transfe rase (FPT) inhibitor that exhibited reasonable pharmacokinetic stabili ty and showed moderate in vivo activity against a variety of tumor cel l lines. The analogous C-11 single compound, pyridylacetamide 2, was f ound to be more potent than 1 in FPT inhibition. Further studies showe d that modification of the ethano bridge of the tricyclic ring system by conversion into a double bond with concomitant introduction of a si ngle bond at C-11 piperidine resulted in compound 3 that had superior FPT activity and pharmacokinetic stability. Compound 4, a 5-bromo-subs tituted analogue of 3, showed improved FPT activity, had good cellular activity, and demonstrated a remarkably improved pharmacokinetic prof ile with AUC of 84.9 and t(1/2) of 82 min. Compound 4 inhibited the gr owth of solid tumor in DLD-1 model by 70% at 50 mpk and 52% at 10 mpk.