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.
MeSH terms
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Benzimidazoles / chemical synthesis
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Benzimidazoles / chemistry*
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Benzimidazoles / pharmacology*
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Computer Simulation
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Crystallography, X-Ray
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Drug Design
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / pharmacology*
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Glycogen Synthase Kinase 3 / antagonists & inhibitors*
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Glycogen Synthase Kinase 3 / metabolism
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Glycogen Synthase Kinase 3 beta
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Nitriles / chemical synthesis
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Nitriles / chemistry*
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Nitriles / pharmacology*
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Oxadiazoles / chemical synthesis
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Oxadiazoles / chemistry*
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Oxadiazoles / pharmacology*
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Structure-Activity Relationship
Substances
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3-(((5-(1-(4-methoxyphenyl)-1H-benzimidazol-6-yl)-1,3,4-oxadiazol-2-yl)sulfanyl)methyl)benzonitrile
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Benzimidazoles
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Enzyme Inhibitors
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Nitriles
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Oxadiazoles
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Glycogen Synthase Kinase 3 beta
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Glycogen Synthase Kinase 3