Probing pockets S2-S4′ of the γ-secretase active site with (hydroxyethyl)urea peptidomimeties

被引：42

作者：

Esler, WP

Das, C

Wolfe, MS ^{[1
]}

机构：

[1] Harvard Univ, Sch Med, Ctr Neurol Dis, Boston, MA 02115 USA

[2] Brigham & Womens Hosp, Boston, MA 02115 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2004年 / 14卷 / 08期

关键词：

D O I：

10.1016/j.bmcl.2004.01.077

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

(Hydroxyethyl)urea peptidomimetics are potent inhibitors of gamma-secretase that are accessible in a few synthetic steps. Systematic alteration of P2-P4' revealed that the corresponding S2-S4' active site pockets accommodate a variety of substituents, consistent with the fact that this protease cleaves a variety of single-pass membrane proteins; however, phenylalanine is not well tolerated at P2'. A compound spanning P2-P3' was identified as a low nM inhibitor of gamma-secretase activity both in cells and under cell-free conditions. (C) 2004 Published by Elsevier Ltd.

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页码：1935 / 1938

页数：4

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