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

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

Affiliation

  • 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.

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