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

被引:41
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
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.
引用
收藏
页码:1935 / 1938
页数:4
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