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Discovery and X-ray crystallographic analysis of a spiropiperidine iminohydantoin inhibitor of beta-secretase.

Abstract：

:A high-throughput screen at 100 microM 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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Barrow JC,Stauffer SR,Rittle KE,Ngo PL,Yang Z,Selnick HG,Graham SL,Munshi S,McGaughey GB,Holloway MK,Simon AJ,Price EA,Sankaranarayanan S,Colussi D,Tugusheva K,Lai MT,Espeseth AS,Xu M,Huang Q,Wolfe A,Pietrak B,Z

doi

10.1021/jm800914n

subject

Has Abstract

pub_date

2008-10-23 00:00:00

pages

6259-62

issue

20

eissn

0022-2623

issn

1520-4804

journal_volume

51

pub_type

杂志文章

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