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American Chemical Society, Journal of Medicinal Chemistry, 24(56), p. 10066-10078, 2013

DOI: 10.1021/jm401466v

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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

Journal article published in 2013 by Valeria La Pietra, Giuseppe La Regina, Antonio Coluccia, Valeria Famiglini, Sveva Pelliccia ORCID, Batya Plotkin, Hagit Eldar-Finkelman, Andrea Brancale, Carlo Ballatore, Alex Crowe, Kurt R. Brunden, Brunden Kr, Luciana Marinelli, Ettore Novellino, Romano Silvestri
This paper was not found in any repository, but could be made available legally by the author.
This paper was not found in any repository, but could be made available legally by the author.

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Abstract

Compound 5 was selected from our in-house library as a suitable starting point for the rational design of new GSK-3 beta inhibitors. MC/FEP calculations of 5 led to the identification of a structural class of new GSK-3 beta inhibitors. Compound 18 inhibited GSK-3 beta with an IC50 of 0.24 microM 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-brain barrier.