Acylguanidines as Small-Molecule β-Secretase Inhibitors
Journal of Medicinal Chemistry2006Vol. 49(21), pp. 6158–6161
Citations Over TimeTop 10% of 2006 papers
Derek C. Cole, Eric S. Manas, Joseph R. Stock, Jeffrey S. Condon, Lee D. Jennings, Ann Aulabaugh, Rajiv Chopra, Rebecca Cowling, John W. Ellingboe, Kristi Fan, Boyd L. Harrison, Yun Hu, Steve Jacobsen, Guixan Jin, Laura Lin, Frank Lovering, Michael S. Malamas, Mark Stahl, James C. Strand, Mohani N. Sukhdeo, Kristine Svenson, M. James Turner, Erik Wagner, Junjun Wu, Ping Zhou, Jonathan Bard
Abstract
BACE1 is an aspartyl protease responsible for cleaving amyloid precursor protein to liberate Abeta, 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 IC(50) = 110 nM).
Related Papers
- → Soluble amyloid precursor protein-α modulates β-secretase activity and amyloid-β generation(2012)172 cited
- → Specific Inhibition of β-Secretase Processing of the Alzheimer Disease Amyloid Precursor Protein(2016)103 cited
- → Infrared and Raman spectra of dl-aspartic acid nitrate monohydrate(1998)38 cited
- → An Empirical Model of γ‐Secretase Activity(2000)4 cited
- → Protease and α-Amylase Inhibitors of Higher Plants(1997)3 cited