Design, Synthesis, and Biological Evaluation of 1-Phenylpyrazolo[3,4-e]pyrrolo[3,4-g]indolizine-4,6(1H,5H)-diones as New Glycogen Synthase Kinase-3β Inhibitors

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• 作者：Valeria La Pietra ; Giuseppe La Regina ; Antonio Coluccia ; Valeria Famiglini ; Sveva Pelliccia ; Batya Plotkin ; Hagit Eldar-Finkelman ; Andrea Brancale ; Carlo Ballatore ; Alex Crowe ; Kurt R. Brunden ; Luciana Marinelli ; Ettore Novellino ; Romano Silvestri
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：December 27, 2013
• 年：2013
• 卷：56
• 期：24
• 页码：10066-10078
• 全文大小：533K
• ISSN：1520-4804

文摘

Compound 5 was selected from our in-house library as a suitable starting point for the rational design of new GSK-3尾 inhibitors. MC/FEP calculations of 5 led to the identication of a structural class of new GSK-3尾 inhibitors. Compound 18 inhibited GSK-3尾 with an IC₅₀ of 0.24 渭M and inhibited tau phosphorylation in a cell-based assay. It proved to be a selective inhibitor of GSK-3 against a panel of 17 kinases and showed >10-fold selectivity against CDK2. Calculated physicochemical properties and Volsurf predictions suggested that compound 18 has the potential to diffuse passively across the blood鈥揵rain barrier.