Discovery and X-ray Crystallographic Analysis of a Spiropiperidine Iminohydantoin Inhibitor of β-Secretase

被引：48

作者：

Barrow, James C. ^{[1
]}

Stauffer, Shaun R. ^{[1
]}

Rittle, Kenneth E. ^{[1
]}

Ngo, Phung L. ^{[1
]}

Yang, ZhiQiang ^{[1
]}

Selnick, Harold G. ^{[1
]}

Graham, Samuel L. ^{[1
]}

Munshi, Sanjeev ^{[2
]}

McGaughey, Georgia B. ^{[3
]}

Holloway, M. Katharine ^{[3
]}

Simon, Adam J. ^{[4
]}

Price, Eric A. ^{[4
]}

Sankaranarayanan, Sethu ^{[4
]}

Colussi, Dennis ^{[4
]}

Tugusheva, Katherine ^{[4
]}

Lai, Ming-Tain ^{[4
]}

Espeseth, Amy S. ^{[4
]}

Xu, Min ^{[4
]}

Huang, Qian ^{[4
]}

Wolfe, Abigail ^{[4
]}

Pietrak, Beth ^{[4
]}

Zuck, Paul ^{[5
]}

Levorse, Dorothy A. ^{[6
]}

Hazuda, Daria ^{[4
]}

Vacca, Joseph P. ^{[1
]}

机构：

[1] Merck Res Labs, Dept Med Chem, West Point, PA 19486 USA

[2] Merck Res Labs, Dept Biol Struct, West Point, PA 19486 USA

[3] Merck Res Labs, Dept Mol Syst, West Point, PA 19486 USA

[4] Merck Res Labs, Dept Alzheimers Res, West Point, PA 19486 USA

[5] Merck Res Labs, Dept Automated Biotechnol, West Point, PA 19486 USA

[6] Merck Res Labs, Dept Mat Characterizat, West Point, PA 19486 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2008年 / 51卷 / 20期

关键词：

D O I：

10.1021/jm800914n

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A high-throughput screen at 100.mu M inhibitor concentration for the BACE-1 enzyme revealed a novel spiropiperidine iminohydantoin aspartyl protease inhibitor template. An X-ray cocrystal structure with BACE-1 revealed a novel mode of binding whereby the inhibitor interacts with the catalytic aspartates via bridging water molecules. Using the crystal structure as a guide, potent compounds with good brain penetration were designed.

引用

页码：6259 / 6262

页数：4

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