Bioorganic & Medicinal Chemistry Letters 2012-04-01

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

Jared N Cumming, 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

Index: Bioorg. Med. Chem. Lett. 22(7) , 2444-9, (2012)

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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.Copyright © 2012 Elsevier Ltd. All rights reserved.