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Bioorg Med Chem Lett. 2010 Mar 15;20(6):1924-7. doi: 10.1016/j.bmcl.2010.01.139. Epub 2010 Feb 2.

Structure-based design and synthesis of novel P2/P3 modified, non-peptidic beta-secretase (BACE-1) inhibitors.

Author information

  • 1Department of Chemistry, Université de Montréal, Montréal, Canada. stephen.hanessian@umontreal.ca

Erratum in

  • Bioorg Med Chem Lett. 2013 Apr 15;23(8):2460-1.


Starting from peptidomimetic BACE-1 inhibitors, the P2 amino acid including the P2/P3 peptide bond was replaced by a rigid 3-aminomethyl cyclohexane carboxylic acid. Co-crystallization revealed an unexpected binding mode with the P3/P4 amide bond placed into the S3 pocket resulting in a new hydrogen bond interaction pattern. Further optimization based on this structure resulted in highly potent BACE-1 inhibitors with selectivity over BACE-2 and cathepsin D.

Copyright 2010 Elsevier Ltd. All rights reserved.

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