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 |
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| Rok vydání: | 1999 |
| Předmět: |
Farnesyl Protein Transferase
Pyridines Protein Prenylation Administration Oral Biological Availability Mice Nude Proto-Oncogene Proteins p21(ras) Mice Structure-Activity Relationship Piperidines Prenylation In vivo Drug Discovery Animals Structure–activity relationship Enzyme Inhibitors Sulfonamides Farnesyl-diphosphate farnesyltransferase Alkyl and Aryl Transferases biology Chemistry Haplorhini Sulfonylurea Compounds Biochemistry Enzyme inhibitor COS Cells biology.protein Molecular Medicine Protein prenylation Cell Division |
| Zdroj: | Journal of Medicinal Chemistry. 42:2651-2661 |
| ISSN: | 1520-4804 0022-2623 |
| 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 |
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