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J Med Chem. 2008 Oct 23;51(20):6259-62. doi: 10.1021/jm800914n. Epub 2008 Sep 24.

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

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  • 1Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.


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.

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