Structure-based optimization of oxadiazole-based GSK-3 inhibitors

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• 作者：Fabio Lo Monte^a ; ^{Fabio.Lo-Monte@gmx.de} ; Thomas Kramer^a ; Jiamin Gu^a ; Martin Brodrecht^a ; Johannes Pilakowski^a ; Ana Fuertes^b ; Juan Manuel Dominguez^b ; Batya Plotkin^c ; Hagit Eldar-Finkelman^c ; Boris Schmidt^a ; ^{schmidt_boris@t-online.de}
• 关键词：Glycogen synthase Kinase-3 (GSK-3) ; Alzheimer's disease ; Structure&ndash ; activity relationship (SAR) ; Reversible inhibition ; Zebrafish phenotype
• 刊名：European Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：March, 2013
• 年：2013
• 卷：61
• 期：Complete
• 页码：26-40
• 全文大小：1260 K

文摘

Inhibition of glycogen synthase kinase-3 (GSK-3) induces neuroprotective effects, e.g. decreases ¦Â-amyloid production and reduces tau hyperphosphorylation, which are both associated with Alzheimer's disease (AD). The two isoforms of GSK-3 in mammalians are GSK-3¦Á and ¦Â, which share 98 % homology in their catalytic domains. We investigated GSK-3 inhibitors based on 2 different scaffolds in order to elucidate the demands of the ATP-binding pocket . Particularly, the oxadiazole scaffold provided potent and selective GSK-3 inhibitors. For example, the most potent inhibitor of the present series, the acetamide 26d, is characterized by an IC₅₀ of 2?nM for GSK-3¦Á and 17?nM for GSK-3¦Â. In addition, the benzodioxane 8g showed up to 27-fold selectivity for GSK-3¦Á over GSK-3¦Â, with an IC₅₀ of 35?nM for GSK-3¦Á. Two GSK-3 inhibitors were further profiled for efficacy and toxicity in the wild-type (wt) zebrafish embryo assay to evaluate simultaneously permeability and safety.