Potent and selective non-cysteine-containing inhibitors of protein farnesyltransferase

  • J Med Chem. 1998 Oct 22;41(22):4288-300. doi: 10.1021/jm980298s.
D J Augeri  1 ,  S J O'Connor ,  D Janowick ,  B Szczepankiewicz ,  G Sullivan ,  J Larsen ,  D Kalvin ,  J Cohen ,  E Devine ,  H Zhang ,  S Cherian ,  B Saeed ,  S C Ng ,  S Rosenberg
Affiliations
  • 1. Departments of Cancer Research, D-47B, and Combinatorial Chemistry, D-4CP, Abbott Laboratories, Abbott Park, Illinois 60064-3500, USA.
PMID: 9784104 DOI: 10.1021/jm980298s
Abstract

Potent and selective non-thiol-containing inhibitors of protein farnesyltransferase are described. FTI-276 (1) was transformed into pyridyl ether analogue 19. The potency of pyridyl ether 19 was improved by modification of the biphenyl core to that of an o-tolyl substituted biphenyl core to give 29. In addition to 0.4 nM in vitro potency, 29 displayed 350 nM potency in whole cells as the parent carboxylic acid. The o-tolyl biphenyl core dramatically and unexpectedly enhanced the potency of other compounds as exemplified by 46, 47, 48, and 49.