Acylguanidines as Small-Molecule β-Secretase Inhibitors
- 15 September 2006
- journal article
- letter
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 49 (21), 6158-6161
- https://doi.org/10.1021/jm0607451
Abstract
BACE1 is an aspartyl protease responsible for cleaving amyloid precursor protein to liberate Aβ, 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).Keywords
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