title: Triazole-linked reduced amide isosteres: an approach for the fragment-based drug discovery of anti-Alzheimer's BACE1 inhibitors.
abstract: In the course of a β-site APP-cleaving enzyme 1 (BACE1) inhibitor discovery project an in situ synthesis/screening protocol was employed to prepare 120 triazole-linked reduced amide isostere inhibitors. Among these compounds, four showed modest (single digit micromolar) BACE1 inhibition. Our ligand design was based on a potent reduced amide isostere 1, wherein the P(2) amide moiety was replaced with an anti-1,2,3-triazole unit. Unfortunately, this replacement resulted in a 1000-fold decrease in potency. Docking studies of triazole-linked reduced amide isostere A3Z10 and potent oxadiazole-linked tertiary carbinamine 2a with BACE1 suggests that the docking poses of A3Z10 and 2a in the active sites are quite similar, with one exception. In the docked structures the placement of the protonated amine that engages D228 differs considerably between 2a and A3Z10. This difference could account for the lower BACE1 inhibition potency of A3Z10 and related compounds relative to 2a.
authors.affiliation: Department of Chemistry, Virginia Tech, Blacksburg, VA 24061, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Monceaux
authors.forename: Chiho
authors.initials: C
authors.lastname: Hirata-Fukae
authors.forename: Polo C-H
authors.initials: PC
authors.lastname: Lam
authors.forename: Maxim M
authors.initials: MM
authors.lastname: Totrov
authors.forename: Yasuji
authors.initials: Y
authors.lastname: Matsuoka
authors.forename: Paul R
authors.initials: PR
authors.lastname: Carlier
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D020134:Catalytic Domain; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D010084:Oxidation-Reduction; D054852:Small Molecule Libraries; D014230:Triazoles / Q000737:chemistry*
chemical_list: D000577:Amides; D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D014230:Triazoles; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human