Design, synthesis and structure–activity relationships of 1,3,4-oxadiazole derivatives as novel inhibitors of glycogen synthase kinase-3β

• Published in: Bioorganic & medicinal chemistry Vol. 17; no. 5; pp. 2017 - 2029
• Main Authors: Saitoh, Morihisa, Kunitomo, Jun, Kimura, Eiji, Hayase, Yoji, Kobayashi, Hiromi, Uchiyama, Noriko, Kawamoto, Tomohiro, Tanaka, Toshimasa, Mol, Clifford D., Dougan, Douglas R., Textor, Garret S., Snell, Gyorgy P., Itoh, Fumio
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01-03-2009; Elsevier
• Subjects: Alzheimer’s disease; Biological and medical sciences; Drug design; GSK-3β; Medical sciences; Neuropharmacology; Oxadiazole; Pharmacology. Drug treatments; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; GSK-3β; Oxadiazole; Drug design; Alzheimer’s disease; Nitrile; Nitrogen heterocycle; Selectivity; Modeling; Structure activity relation; Molecular model; Bicyclic compound; Oxadiazole derivatives; Binding mode; CSK-3β; Aromatic compound; Chemical synthesis; Alzheimer's disease; Oxygen nitrogen heterocycle; Tau-protein kinase; Enzyme; Transferases; Benzene derivatives; Enzyme inhibitor; Inhibitor enzyme complex; Antialzheimer agent; In vitro; Benzimidazole derivatives
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2009.01.019

Design, synthesis and structure–activity relationships of novel oxadiazole derivatives as GSK-3β inhibitors are reported.
Glycogen synthase kinase-3β (GSK-3β) 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-3β inhibitors. Among these inhibitors, compound
20x showed highly selective and potent GSK-3β inhibitory activity in vitro and its binding mode was determined by obtaining the X-ray co-crystal structure of
20x and GSK-3β.