2-(2-Aminothiazol-4-yl)pyrrolidine-based tartrate diamides as potent, selective and orally bioavailable TACE inhibitors

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• 作者：Chaoyang Dai^a ; ^{chaoyang.dai@merck.com"" rel=""nofollow} ; ^{chaoyangdai@hotmail.com"" rel=""nofollow} ; Dansu Li^a ; Janeta Popovici-Muller^a ; Lianyun Zhao^a ; Vinay M. Girijavallabhan^b ; Kristin E. Rosner^a ; Brian J. Lavey^b ; Razia Rizvi^b ; Bandarpalle B. Shankar^b ; Michael K.C. Wong^b ; Zhuyan Guo^b ; Peter Orth^b ; Corey O. Strickland^b ; Jing Sun^c ; Xiaoda Niu^c ; Shiying Chen^d ; Joseph A. Kozlowski^b ; Daniel J. Lundell^c ; John J. Piwinski^a ; Neng-Yang Shih^a ; M. Arshad Siddiqui^a
• 关键词：TNF-α ; converting enzyme ; TACE tartrate ; Zinc binding group (R)-2-(2-N-alkylaminothiazol-4-yl)pyrrolidines
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2011
• 出版时间：15 May 2011
• 年：2011
• 卷：21
• 期：10
• 页码：3172-3176
• 全文大小：1967 K

文摘

TNF-α converting enzyme (TACE) inhibitors are promising agents to treat inflammatory disorders and cancer. We have investigated novel tartrate diamide TACE inhibitors where the tartrate core binds to zinc in a unique tridentate fashion. Incorporating (R)-2-(2-N-alkylaminothiazol-4-yl)pyrrolidines into the left hand side amide of the tartrate scaffold led to the discovery of potent and selective TACE inhibitors, some of which exhibited good rat oral bioavailability.