title: Design, synthesis and structure-activity relationships of 1,3,4-oxadiazole derivatives as novel inhibitors of glycogen synthase kinase-3beta.
abstract: 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.
authors.affiliation: Pharmaceutical Research Division, Medicinal Chemistry Research Laboratories, Takeda Pharmaceutical Company, Ltd, Osaka, Japan. Saitoh_Morihisa@takeda.co.jp
authors.forename: Morihisa
authors.initials: M
authors.lastname: Saitoh
authors.forename: Jun
authors.initials: J
authors.lastname: Kunitomo
authors.forename: Eiji
authors.initials: E
authors.lastname: Kimura
authors.forename: Yoji
authors.initials: Y
authors.lastname: Hayase
authors.forename: Hiromi
authors.initials: H
authors.lastname: Kobayashi
authors.forename: Noriko
authors.initials: N
authors.lastname: Uchiyama
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kawamoto
authors.forename: Toshimasa
authors.initials: T
authors.lastname: Tanaka
authors.forename: Clifford D
authors.initials: CD
authors.lastname: Mol
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Dougan
authors.forename: Garret S
authors.initials: GS
authors.lastname: Textor
authors.forename: Gyorgy P
authors.initials: GP
authors.lastname: Snell
authors.forename: Fumio
authors.initials: F
authors.lastname: Itoh
mesh_terms: 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
chemical_list: 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