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Discovery of novel hydroxamates as highly potent tumor necrosis factor-alpha converting enzyme inhibitors. Part II: optimization of the S3' pocket |
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| Authors: | Mazzola Robert D Zhu Zhaoning Sinning Lisa McKittrick Brian Lavey Brian Spitler James Kozlowski Joseph Neng-Yang Shih Zhou Guowei Guo Zhuyan Orth Peter Madison Vincent Sun Jing Lundell Daniel Niu Xiaoda |
| Institution: | Department of Medicinal Chemistry, Schering Plough Research Institute, Kenilworth, NJ 07033, USA. robert.mazzola@spcorp.com |
| Abstract: | A series of cyclopropyl hydroxamic acids were prepared. Many of the compounds displayed picomolar affinity for the TACE enzyme while maintaining good to excellent selectivity profiles versus MMP-1, -2, -3, -7, -14, and ADAM-10. X-ray analysis of an inhibitor in the TACE active site indicated that the molecules bound to the enzyme in the S1'-S3' pocket. |
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