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

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2006年 / 49卷 / 21期

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).

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页码：6158 / 6161

页数：4

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