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2-(2-Aminothiazol-4-yl)pyrrolidine-based tartrate diamides as potent, selective and orally bioavailable TACE inhibitors |
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| Authors: | Dai Chaoyang Li Dansu Popovici-Muller Janeta Zhao Lianyun Girijavallabhan Vinay M Rosner Kristin E Lavey Brian J Rizvi Razia Shankar Bandarpalle B Wong Michael K C Guo Zhuyan Orth Peter Strickland Corey O Sun Jing Niu Xiaoda Chen Shiying Kozlowski Joseph A Lundell Daniel J Piwinski John J Shih Neng-Yang Siddiqui M Arshad |
| Institution: | a Department of Chemistry, Merck Research Laboratories, 320 Bent Street, Cambridge, MA 02141, USA b Department of Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033-0539, USA c Department of Inflammation, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033-0539, USA d Department of Exploratory Drug Metabolism and Pharmacokinetics, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033-0539, USA |
| 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. |
| Keywords: | TNF-α converting enzyme TACE tartrate Zinc binding group (R)-2-(2-N-alkylaminothiazol-4-yl)pyrrolidines |
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