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

La Pietra, Valeria, La Regina, Giuseppe, Coluccia, Antonio, Famiglini, Valeria, Pelliccia, Sveva, Plotkin, Batya, Eldar-Finkelman, Hagit, Brancale, Andrea ORCID: https://orcid.org/0000-0002-9728-3419, Ballatore, Carlo, Crowe, Alex, Brunden, Kurt R., Marinelli, Luciana, Novellino, Ettore and Silvestri, Romano 2013. 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 of Medicinal Chemistry 56 (24) , pp. 10066-10078. 10.1021/jm401466v

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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-3β inhibitors. MC/FEP calculations of 5 led to the identication of a structural class of new GSK-3β inhibitors. Compound 18 inhibited GSK-3β with an IC50 of 0.24 μM 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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Pharmacy
Subjects:	R Medicine > RS Pharmacy and materia medica
Publisher:	American Chemical Society
ISSN:	0022-2623
Last Modified:	05 Jan 2024 05:54
URI:	https://orca.cardiff.ac.uk/id/eprint/56813

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