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

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Saitoh M, Kunitomo J, Kimura E, Hayase Y, Kobayashi H, Uchiyama N, Kawamoto T, Tanaka T, Mol CD, Dougan DR, Textor GS, Snell GP, Itoh F

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

Bioorg Med Chem. 2009 Mar 1;17(5):2017-29. doi: 10.1016/j.bmc.2009.01.019. Epub 2009 Jan 15.

PubMed ID

19200745 [ View in PubMed

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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.

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Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
2-(1,3-benzodioxol-5-yl)-5-[(3-fluoro-4-methoxybenzyl)sulfanyl]-1,3,4-oxadiazole	Glycogen synthase kinase-3 beta	IC 50 (nM)	65	7.5	37	Details