Discovery and X-ray Crystallographic Analysis of a Spiropiperidine Iminohydantoin Inhibitor of β-Secretase
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- 作者：James C. Barrow ; Shaun R. Stauffer ; Kenneth E. Rittle ; Phung L. Ngo ; ZhiQiang Yang ; Harold G. Selnick ; Samuel L. Graham ; Sanjeev Munshi ; Georgia B. McGaughey ; M. Katharine Holloway ; Adam J. Simon ; Eri
- 刊名：Journal of Medicinal Chemistry
- 出版年：2008
- 出版时间：October 23, 2008
- 年：2008
- 卷：51
- 期：20
- 页码：6259-6262
- 全文大小：156K
- 年卷期：v.51,no.20(October 23, 2008)
- ISSN：1520-4804
文摘
A high-throughput screen at 100 μM 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.