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.
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 / V., La Pietra; LA REGINA, Giuseppe; Coluccia, Antonio; Famiglini, Valeria; S., Pelliccia; B., Plotkin; H., Eldar Finkelman; A., Brancale; C., Ballatore; A., Crowe; Kr, Brunden; L., Marinelli; E., Novellino; Silvestri, Romano. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - STAMPA. - 56:(2013), pp. 10066-10078. [10.1021/jm401466v]
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 REGINA, GIUSEPPE
;COLUCCIA, Antonio;FAMIGLINI, VALERIA;SILVESTRI, Romano
2013
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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
