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

  • J Med Chem. 1999 Jul 15;42(14):2651-61. doi: 10.1021/jm990059k.
A G Taveras  1 ,  J Deskus ,  J Chao ,  C J Vaccaro ,  F G Njoroge ,  B Vibulbhan ,  P Pinto ,  S Remiszewski ,  J del Rosario ,  R J Doll ,  C Alvarez ,  T Lalwani ,  A K Mallams ,  R R Rossman ,  A Afonso ,  V M Girijavallabhan ,  A K Ganguly ,  B Pramanik ,  L Heimark ,  W R Bishop ,  L Wang ,  P Kirschmeier ,  L James ,  D Carr ,  M Liu
Affiliations
  • 1. Anti-infectives and Tumor Biology Research, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, USA.
PMID: 10411485 DOI: 10.1021/jm990059k
Abstract

Farnesyl protein transferase (FPT) is a promising target for the development of Cancer chemotherapeutics because it is responsible for the farnesylation of oncogenic p21 Ras proteins which are found in nearly 30% of all human cancers and necessary for cellular development and growth. The recent discovery and progression to phase II clinical trials of trihalobenzocycloheptapyridine Sch-66336 as a potent inhibitor of FPT with oral, in vivo efficacy in mice have spawned extensive structure-activity relationship studies (SAR) of this class of compounds. Of the many trihalobenzocycloheptapyridine analogues prepared, we have identified several which inhibit FPT and cellular proliferation at single-digit nanomolar concentrations and which have good pharmacokinetic properties in mice.