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

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• 作者：Morihisa Saitoh ; 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
• 关键词：GSK-3β ; Alzheimer’ ; s disease ; Oxadiazole ; Drug design
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2009
• 出版时间：1 March 2009
• 年：2009
• 卷：17
• 期：5
• 页码：2017-2029
• 全文大小：625 K

文摘

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.