title: Novel non-peptidic and small-sized BACE1 inhibitors.
abstract: Recently, we reported substrate-based beta-secretase (BACE1) inhibitors with a hydroxymethylcarbonyl (HMC) isostere as a substrate transition-state mimic. These inhibitors showed potent BACE1 inhibitory activities (approximately 1.2 nM IC(50)). In order to improve in vivo enzymatic stability and permeability across the blood-brain barrier, these penta-peptidic inhibitors would need to be further optimized. On the other hand, non-peptidic inhibitors possessing isophthalic residue at the P(2) position were reported from other research groups. We selected isophthalic-type aromatic residues at the P(2) position and an HMC isostere at the P(1) position as lead compounds. On the basis of the design approach focused on the conformer of docked inhibitor in BACE1, we found novel non-peptidic and small-sized BACE1 inhibitors possessing a 2,6-pyridinedicarboxylic, chelidamic or chelidonic residue at the P(2) position.
authors.affiliation: Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science and 21st Century COE Program, Kyoto Pharmaceutical University, Kyoto 607-8412, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hamada
authors.forename: Hiroko
authors.initials: H
authors.lastname: Ohta
authors.forename: Naoko
authors.initials: N
authors.lastname: Miyamoto
authors.forename: Ryoji
authors.initials: R
authors.lastname: Yamaguchi
authors.forename: Abdellah
authors.initials: A
authors.lastname: Yamani
authors.forename: Koushi
authors.initials: K
authors.lastname: Hidaka
authors.forename: Tooru
authors.initials: T
authors.lastname: Kimura
authors.forename: Kazuki
authors.initials: K
authors.lastname: Saito
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Shoichi
authors.initials: S
authors.lastname: Ishiura
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kiso
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D015394:Molecular Structure; D009842:Oligopeptides / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D009842:Oligopeptides; D053829:Amyloid Precursor Protein Secretases