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

Stephen Hanessian; Zhihui Shao; Claudia Betschart; Jean-Michel Rondeau; Ulf Neumann; Marina Tintelnot-Blomley

doi:10.1016/j.bmcl.2010.01.139

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

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

Authors

Stephen Hanessian¹, Zhihui Shao, Claudia Betschart, Jean-Michel Rondeau, Ulf Neumann, Marina Tintelnot-Blomley

Affiliation

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

PMID: 20172717
DOI: 10.1016/j.bmcl.2010.01.139

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amyloid Precursor Protein Secretases / antagonists & inhibitors*
Aspartic Acid Endopeptidases / antagonists & inhibitors*
Crystallization
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / pharmacology*
Hydrogen Bonding
Models, Molecular
Molecular Structure

Substances

Enzyme Inhibitors
Amyloid Precursor Protein Secretases
Aspartic Acid Endopeptidases
BACE1 protein, human