Bioorganic & Medicinal Chemistry Letters 2011-05-15

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

Chaoyang Dai, Dansu Li, Janeta Popovici-Muller, Lianyun Zhao, Vinay M Girijavallabhan, Kristin E Rosner, Brian J Lavey, Razia Rizvi, Bandarpalle B Shankar, Michael K C Wong, Zhuyan Guo, Peter Orth, Corey O Strickland, Jing Sun, Xiaoda Niu, Shiying Chen, Joseph A Kozlowski, Daniel J Lundell, John J Piwinski, Neng-Yang Shih, M Arshad Siddiqui

Index: Bioorg. Med. Chem. Lett. 10th ed., 21 , 3172-3176, (2011)

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Abstract

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.Copyright © 2011. Published by Elsevier Ltd.