Design and synthesis of statine-based cell-permeable peptidomimetic inhibitors of human β-secretase

被引：89

作者：

Hom, RK ^{[1
]}

Fang, LY ^{[1
]}

Mamo, S ^{[1
]}

Tung, JS ^{[1
]}

Guinn, AC ^{[1
]}

Walker, DE ^{[1
]}

Davis, DL ^{[1
]}

Gailunas, AF ^{[1
]}

Thorsett, ED ^{[1
]}

Sinha, S ^{[1
]}

Knops, JE ^{[1
]}

Jewett, NE ^{[1
]}

Anderson, JP ^{[1
]}

John, V ^{[1
]}

机构：

[1] Elan Pharmaceut, San Francisco, CA 94080 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2003年 / 46卷 / 10期

关键词：

D O I：

10.1021/jm025619l

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We describe the development of statine-based peptidomimetic inhibitors of human beta-secretase (BACE). The conversion of the peptide inhibitor 1 into cell-permeable peptidomimetic inhibitors of BACE was achieved through an iterative strategy of conceptually subdividing 1 into three regions: an N-terminal portion, a central statine-containing core, and a C-terminus. Replacement of the amino acid residues of 1 with moieties with less peptidic character was done with retention of BACE enzyme inhibitory activity. This approach led to the identification of the cell-permeable BACE inhibitor 38 that demonstrated BACE-mechanism-selective inhibition of Abeta secretion in human embryonic kidney cells.

引用

页码：1799 / 1802

页数：4

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