Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 49, Issue 21, Pages 6158-6161Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm0607451
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BACE1 is an aspartyl protease responsible for cleaving amyloid precursor protein to liberate A beta, which aggregates leading to plaque deposits implicated in Alzheimer's disease. We have identified small-molecule acylguanidine inhibitors of BACE1. Crystallographic studies show that these compounds form unique hydrogen-bonding interactions with the catalytic site aspartic acids and stabilize the protein in a flap-open conformation. Structure-based optimization led to the identification of potent analogs, such as 10d (BACE1 IC50 = 110 nM).
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