Potent, Cell Active, Non-Thiol Tetrapeptide Inhibitors of Farnesyltransferase

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• 作者：John T. Hunt ; Ving G. Lee ; Katerina Leftheris ; Bernd Seizinger ; Joan Carboni ; John Mabus ; Carol Ricca ; Ning Yan ; and Veeraswamy Manne
• 刊名：Journal of Medicinal Chemistry
• 出版年：1996
• 出版时间：January 19, 1996
• 年：1996
• 卷：39
• 期：2
• 页码：353 - 358
• 全文大小：147K
• 年卷期：v.39,no.2(January 19, 1996)
• ISSN：1520-4804

文摘

All previously reported CAAX-based farnesyltransferase inhibitorscontain a thiol functionality.We report that attachment of the 4-imidazolyl group, via 1-, 2-,or 3-carbon alkyl or alkanoylspacers, to Val-Tic-Met or tLeu-Tic-Gln provides potent FT inhibitors.(R*)-N-[[1,2,3,4-Tetrahydro-2-[N-[2-(1H-imidazol-4-yl)ethyl]-L-valyl]-3-isoquinolinyl]carbonyl]-L-methionine([imidazol-4-yl-ethyl]-Val-Tic-Met), with FT IC₅₀ = 0.79 nM,displayed potent cell activity in theabsence of prodrug formation (SAG EC₅₀ = 3.8M).