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Structure based design of iminohydantoin BACE1 inhibitors: identification of an orally available, centrally active BACE1 inhibitor |
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| Authors: | Cumming Jared N Smith Elizabeth M Wang Lingyan Misiaszek Jeffrey Durkin James Pan Jianping Iserloh Ulrich Wu Yusheng Zhu Zhaoning Strickland Corey Voigt Johannes Chen Xia Kennedy Matthew E Kuvelkar Reshma Hyde Lynn A Cox Kathleen Favreau Leonard Czarniecki Michael F Greenlee William J McKittrick Brian A Parker Eric M Stamford Andrew W |
| Institution: | Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA. jared.cumming@merck.com |
| Abstract: | From an initial lead 1, a structure-based design approach led to identification of a novel, high-affinity iminohydantoin BACE1 inhibitor that lowers CNS-derived Aβ following oral administration to rats. Herein we report SAR development in the S3 and F' subsites of BACE1 for this series, the synthetic approaches employed in this effort, and in vivo data for the optimized compound. |
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