title: 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.
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 identification 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.
authors.affiliation: Dipartimento di Farmacia, Università di Napoli Federico II , Via Domenico Montesano 49, I-80131 Napoli, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: La Pietra
authors.forename: Giuseppe
authors.initials: G
authors.lastname: La Regina
authors.forename: Antonio
authors.initials: A
authors.lastname: Coluccia
authors.forename: Valeria
authors.initials: V
authors.lastname: Famiglini
authors.forename: Sveva
authors.initials: S
authors.lastname: Pelliccia
authors.forename: Batya
authors.initials: B
authors.lastname: Plotkin
authors.forename: Hagit
authors.initials: H
authors.lastname: Eldar-Finkelman
authors.forename: Andrea
authors.initials: A
authors.lastname: Brancale
authors.forename: Carlo
authors.initials: C
authors.lastname: Ballatore
authors.forename: Alex
authors.initials: A
authors.lastname: Crowe
authors.forename: Kurt R
authors.initials: KR
authors.lastname: Brunden
authors.forename: Luciana
authors.initials: L
authors.lastname: Marinelli
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Romano
authors.initials: R
authors.lastname: Silvestri
mesh_terms: D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D054836:Indolizidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship; D013388:Succinimides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C586723:1-(2',4'-dichlorophenyl)-3-methylpyrazolo(3,4-e)pyrrolo(3,4-g)indolizine-4,6(1H,5H)-dione; D054836:Indolizidines; D047428:Protein Kinase Inhibitors; D011994:Recombinant Proteins; D013388:Succinimides; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3