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.
Morihisa Saitoh  1 ,  Jun Kunitomo ,  Eiji Kimura ,  Yoji Hayase ,  Hiromi Kobayashi ,  Noriko Uchiyama ,  Tomohiro Kawamoto ,  Toshimasa Tanaka ,  Clifford D Mol ,  Douglas R Dougan ,  Garret S Textor ,  Gyorgy P Snell ,  Fumio Itoh
Affiliations
  • 1. Pharmaceutical Research Division, Medicinal Chemistry Research Laboratories, Takeda Pharmaceutical Company, Ltd, Osaka, Japan. [email protected]
PMID: 19200745 DOI: 10.1016/j.bmc.2009.01.019
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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