Acylguanidines as small-molecule β-secretase inhibitors

被引:95
作者
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
机构
[1] Wyeth Ayerst Res, Pearl River, NY 10965 USA
[2] Wyeth Ayerst Res, Cambridge, MA 02139 USA
[3] Wyeth Ayerst Res, Princeton, NJ 08852 USA
[4] Wyeth Ayerst Res, Collegeville, PA 19426 USA
关键词
D O I
10.1021/jm0607451
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
BACE1 is an aspartyl protease responsible for cleaving amyloid precursor protein to liberate A beta, 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 optimization led to the identification of potent analogs, such as 10d (BACE1 IC50 = 110 nM).
引用
收藏
页码:6158 / 6161
页数:4
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