Design and synthesis of potent beta-secretase (BACE1) inhibitors with P1' carboxylic acid bioisosteres.
Recently, we reported potent and small-sized beta-secretase (BACE1) inhibitors KMI-420 and KMI-429 in which we replaced the Glu residue at the P4 position of KMI-260 and KMI-360, respectively, with a 1H-tetrazole-5-carbonyl DAP (L-alpha,beta-diaminopropionic acid) residue. At the P1' position, these compounds contain one or two carboxylic acid groups, which are unfavorable for crossing the blood-brain barrier. Herein, we report BACE1 inhibitors with P1' carboxylic acid bioisosteres in order to develop practical anti-Alzheimer's disease drugs. Among them, tetrazole ring-containing compounds, KMI-570 (IC50=4.8 nM) and KMI-684 (IC50=1.2 nM), exhibited significantly potent BACE1 inhibitory activities.
Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science and 21st Century COE Program, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan.
Tooru
T
Kimura
Yoshio
Y
Hamada
Monika
M
Stochaj
Hayato
H
Ikari
Ayaka
A
Nagamine
Hamdy
H
Abdel-Rahman
Naoto
N
Igawa
Koushi
K
Hidaka
Jeffrey-Tri
JT
Nguyen
Kazuki
K
Saito
Yoshio
Y
Hayashi
Yoshiaki
Y
Kiso
D000544:Alzheimer Disease / Q000188:drug therapy; D053829:Amyloid Precursor Protein Secretases; D002264:Carboxylic Acids / Q000737:chemistry*; D018360:Crystallography, X-Ray; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D010450:Endopeptidases / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D002264:Carboxylic Acids; D004791:Enzyme Inhibitors; C500029:KMI-420; C500030:KMI-429; D009842:Oligopeptides; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases