title: BACE1 inhibitors: optimization by replacing the P1' residue with non-acidic moiety.
abstract: Recently, we reported potent BACE1 inhibitors KMI-429, -684, and -574 possessing a hydroxymethylcarbonyl isostere as a substrate transition-state mimic. These inhibitors showed potent inhibitory activities in enzymatic and cell assays, especially, KMI-429 was confirmed to significantly inhibit Abeta production in vivo. However, acidic moieties at the P(4) and P(1)' positions of KMI-compounds were thought to be unfavorable for membrane permeability across the blood-brain barrier. Herein, we replaced acidic moieties at the P(4) position with other hydrogen bond acceptor groups, and these inhibitors exhibited improved BACE1 inhibitory activities in cultured cells. In this study, we replaced the acidic moieties at the P(1)' position with non-acidic and low molecular sized moieties.
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: Hamdy
authors.initials: H
authors.lastname: Abdel-Rahman
authors.forename: Abdellah
authors.initials: A
authors.lastname: Yamani
authors.forename: Jeffrey-Tri
authors.initials: JT
authors.lastname: Nguyen
authors.forename: Monika
authors.initials: M
authors.lastname: Stochaj
authors.forename: Koushi
authors.initials: K
authors.lastname: Hidaka
authors.forename: Tooru
authors.initials: T
authors.lastname: Kimura
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Kazuki
authors.initials: K
authors.lastname: Saito
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