Structure based design of iminohydantoin BACE1 inhibitors: Identification of an orally available, centrally active BACE1 inhibitor

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• 作者：Jared N. Cumming ; ^&dagger ; ; ^{jared.cumming@merck.com} ; Elizabeth M. Smith ; Lingyan Wang ; Jeffrey Misiaszek ; James Durkin ; Jianping Pan ; Ulrich Iserloh ; Yusheng Wu ; Zhaoning Zhu ; Corey Strickland ; Johannes Voigt ; Xia Chen ; Matthew E. Kennedy ; Reshma Kuvelkar ; Lynn A. Hyde ; Kathleen Cox ; Leonard Favreau ; Michael F. Czarniecki ; William J. Greenlee ; Brian A. McKittrick ; Eric M. Parker ; Andrew W. Stamford ; ^&Dagger ; ; ^{andrew.stamford@merck.com}
• 关键词：BACE ; 尾-Secretase ; Alzheimer&prime ; s disease ; Iminohydantoin ; In vivo
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 期刊代码：10_0960894x
• 类别：ch
• 出版时间：1 April, 2012
• 卷：22
• 期：7
• 页码：2444-2449
• 文件大小：716 K

摘要

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 A尾 following oral administration to rats. Herein we report SAR development in the S3 and F鈥?subsites of BACE1 for this series, the synthetic approaches employed in this effort, and in vivo data for the optimized compound.