Identification of Pharmacokinetically Stable 3,10-Dibromo-8-chlorobenzocycloheptapyridine Farnesyl Protein Transferase Inhibitors with Potent Enzyme and Cellular Activities

Autor: Carmen S. Alvarez, Taveras Arthur G, Bancha Vibulbhan, Doll Ronald J, Viyyoor M. Girijavallabhan, Birendra N. Pramanik, Mathew S. Bryant, Donna Carr, Ashit K. Ganguly, Linda James, Alan K. Mallams, Chao Jianping, Adriano Afonso, Jeff Deskus, Ming Liu, Lynn Wang, Randall R. Rossman, Lalwani Tarik, Paul Kirschmeier, Cynthia J. Vaccaro, Larry Heimark, Stacy W. Remiszewski, F. George Njoroge, W. Robert Bishop, Robert Patton, Jocelyn del Rosario, Pat Pinto, and Amin A. Nomeir
Rok vydání: 1999
Předmět:
Zdroj: Journal of Medicinal Chemistry. 42:2651-2661
ISSN: 1520-4804
0022-2623
DOI: 10.1021/jm990059k
Popis: 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.
Databáze: OpenAIRE