(+)-4-[2-[4-(8-Chloro-3,10-dibromo-6,11-dihydro-5H-benzo[5, 6]cyclohepta[1,2-b]- pyridin-11(R)-yl)-1-piperidinyl]-2-oxo-ethyl]-1-piperidinecarboxamid e (SCH-66336): a very potent farnesyl protein transferase inhibitor as a novel antitumor agent
| Autor: | Andrew T. McPhail, Kelly Joseph M, Joycelyn del Rosario, James Wang, Ronald Wolin, Arthur G. Taveras, Alan K. Mallams, Stacy Remiszewski, C.-C. Lin, W. Robert Bishop, and Viyyoor M. Girijavallabhan, P. Kirschmeier, Carmen S. Alvarez, J. Desai, Lynn Wang, Jeffrey Deskus, Cooper Alan B, Michael Connolly, Adriano Afonso, F. George Njoroge, P. Pinto, Y. Liu, Ming Liu, B. Vibulbhan, Robert Patton, Dinananth F. Rane, Amin A. Nomeir, Jesse Wong, Ronald J. Maplewood Doll, Randall R. Rossman, Mathew S. Bryant, A. K. Ganguly |
|---|---|
| Rok vydání: | 1998 |
| Předmět: |
Farnesyl Protein Transferase
medicine.drug_class Stereochemistry Pyridines Protein Prenylation Mice Nude Carboxamide Antineoplastic Agents Chemical synthesis Mice Structure-Activity Relationship Piperidines Drug Discovery medicine Tumor Cells Cultured Structure–activity relationship Animals Humans Enzyme Inhibitors chemistry.chemical_classification Farnesyl-diphosphate farnesyltransferase Alkyl and Aryl Transferases biology Stereoisomerism Macaca fascicularis chemistry Enzyme inhibitor COS Cells biology.protein Molecular Medicine Protein prenylation Drug Screening Assays Antitumor Tricyclic |
| Zdroj: | Journal of medicinal chemistry. 41(24) |
| ISSN: | 0022-2623 |
| Popis: | We have previously shown that appropriate modification of the benzocycloheptapyridine tricyclic ring system can provide potent farnesyl protein transferase (FPT) inhibitors with good cellular activity. Our laboratories have also established that incorporation of either pyridinylacetyl N-oxide or 4-N-carboxamidopiperidinylacetyl moieties results in pharmacokinetically stable inhibitors that are orally efficacious in nude mice. We now demonstrate that further elaboration of the tricyclic ring system by introducing a bromine atom at the 7- or the 10-position of the 3-bromo-8-chlorotricyclic ring system provides compounds that have superior potency and selectivity in FPT inhibition. These compounds have good serum levels and half-lives when given orally to rodents and primates. In vitro and in vivo evaluation of a panel of these inhibitors has led to identification of 15 (SCH 66336) as a highly potent (IC50 = 1.9 nM) antitumor agent that is currently undergoing human clinical trials. |
| Databáze: | OpenAIRE |
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