title: Structure-based design and synthesis of novel P2/P3 modified, non-peptidic beta-secretase (BACE-1) inhibitors.
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.
authors.affiliation: Department of Chemistry, Université de Montréal, Montréal, Canada. stephen.hanessian@umontreal.ca
authors.forename: Stephen
authors.initials: S
authors.lastname: Hanessian
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Shao
authors.forename: Claudia
authors.initials: C
authors.lastname: Betschart
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Rondeau
authors.forename: Ulf
authors.initials: U
authors.lastname: Neumann
authors.forename: Marina
authors.initials: M
authors.lastname: Tintelnot-Blomley
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D003460:Crystallization; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006860:Hydrogen Bonding; D008958:Models, Molecular; D015394:Molecular Structure
chemical_list: D004791:Enzyme Inhibitors; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human