Probing pockets S2–S4′ of the γ-secretase active site with (hydroxyethyl)urea peptidomimetics
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- 作者：Esler ; William P. ; Das ; Chittaranjan ; Wolfe ; Michael S.
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：2004
- 出版时间：April 19, 2004
- 年：2004
- 卷：14
- 期：8
- 页码：1935-1938
- 全文大小：169 K
文摘
(Hydroxyethyl)urea peptidomimetics are potent inhibitors of γ-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 γ-secretase activity both in cells and under cell-free conditions.