BACE1 inhibitors: optimization by replacing the P1' residue with non-acidic moiety.
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.
Hamada
Yoshio
Y
Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science and 21st Century COE Program, Kyoto Pharmaceutical University, Kyoto 607-8412, Japan.
Abdel-Rahman
Hamdy
H
Yamani
Abdellah
A
Nguyen
Jeffrey-Tri
JT
Stochaj
Monika
M
Hidaka
Koushi
K
Kimura
Tooru
T
Hayashi
Yoshio
Y
Saito
Kazuki
K
Ishiura
Shoichi
S
Kiso
Yoshiaki
Y
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D015394:Molecular Structure; D009842:Oligopeptides / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D009842:Oligopeptides; D053829:Amyloid Precursor Protein Secretases