Novel non-peptidic and small-sized BACE1 inhibitors.
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.
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.
Ohta
Hiroko
H
Miyamoto
Naoko
N
Yamaguchi
Ryoji
R
Yamani
Abdellah
A
Hidaka
Koushi
K
Kimura
Tooru
T
Saito
Kazuki
K
Hayashi
Yoshio
Y
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