Acylguanidines as small-molecule β-secretase inhibitors

…, A Aulabaugh, R Chopra, R Cowling…

Index: Cole, Derek C.; Manas, Eric S.; Stock, Joseph R.; Condon, Jeffrey S.; Jennings, Lee D.; Aulabaugh, Ann; Chopra, Rajiv; Cowling, Rebecca; Ellingboe, John W.; Fan, Kristi Y.; Harrison, Boyd L.; Hu, Yun; Jacobsen, Steve; Jin, Guixan; Lin, Laura; Lovering, Frank E.; Malamas, Michael S.; Stahl, Mark L.; Strand, James; Sukhdeo, Mohani N.; Svenson, Kristine; Turner, M. James; Wagner, Erik; Wu, Junjun; Zhou, Ping; Bard, Jonathan Journal of Medicinal Chemistry, 2006 ,  vol. 49,  # 21  p. 6158 - 6161

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Citation Number: 97

Abstract

BACE1 is an aspartyl protease responsible for cleaving amyloid precursor protein to liberate Aβ, which aggregates leading to plaque deposits implicated in Alzheimer's disease. We have identified small-molecule acylguanidine inhibitors of BACE1. Crystallographic studies show that these compounds form unique hydrogen-bonding interactions with the catalytic site aspartic acids and stabilize the protein in a flap-open conformation. Structure-based ...