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J Med Chem. 2004 Jan 1;47(1):158-64.

Design and synthesis of hydroxyethylene-based peptidomimetic inhibitors of human beta-secretase.

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  • 1Elan, 800 Gateway Boulevard, South San Francisco, California 94080, USA.


The hydroxyethylene (HE) transition state isostere was developed as a scaffold to provide potent, small molecule inhibitors of human beta-secretase (BACE). The previous work on the statine series proved critical to the discovery of HE structure-activity relationships. Compound 20 with the N-terminal isophthalamide proved to be the most potent HE inhibitor (IC(50) = 30 nM) toward BACE. Unlike the statine series, we identified HE inhibitors without carboxylic acids on the C terminus, leading to enhanced cell penetration and making them attractive candidates for further drug development in Alzheimer's disease.

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