Design, synthesis and structure-activity relationships of 1,3,4-oxadiazole derivatives as novel inhibitors of glycogen synthase kinase-3beta.
Glycogen synthase kinase-3beta (GSK-3beta) is implicated in abnormal hyperphosphorylation of tau protein and its inhibitors are expected to be a promising therapeutic agents for the treatment of Alzheimer's disease. Here we report design, synthesis and structure-activity relationships of a novel series of oxadiazole derivatives as GSK-3beta inhibitors. Among these inhibitors, compound 20x showed highly selective and potent GSK-3beta inhibitory activity in vitro and its binding mode was determined by obtaining the X-ray co-crystal structure of 20x and GSK-3beta.
Saitoh
Morihisa
M
Pharmaceutical Research Division, Medicinal Chemistry Research Laboratories, Takeda Pharmaceutical Company, Ltd, Osaka, Japan. Saitoh_Morihisa@takeda.co.jp
Kunitomo
Jun
J
Kimura
Eiji
E
Hayase
Yoji
Y
Kobayashi
Hiromi
H
Uchiyama
Noriko
N
Kawamoto
Tomohiro
T
Tanaka
Toshimasa
T
Mol
Clifford D
CD
Dougan
Douglas R
DR
Textor
Garret S
GS
Snell
Gyorgy P
GP
Itoh
Fumio
F
D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D009570:Nitriles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
C540819:3-(((5-(1-(4-methoxyphenyl)-1H-benzimidazol-6-yl)-1,3,4-oxadiazol-2-yl)sulfanyl)methyl)benzonitrile; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D009570:Nitriles; D010069:Oxadiazoles; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3