title: Identification of 2-(4-pyridyl)thienopyridinones as GSK-3β inhibitors.
abstract: The discovery of a novel series of 2-(4-pyridyl)thienopyridinone GSK-3β inhibitors is reported. X-ray crystallography reveals its binding mode and enables rationalization of the SAR. The initial optimization of the template for improved cellular activity and predicted CNS penetration is also presented.
authors.affiliation: Department of Medicinal Chemistry, Neuroscience Centre of Excellence of Drug Discovery, GlaxoSmithKline, Via A Fleming 4, 37135 Verona, Italy. gabriella.gentile@aptuit.com
authors.forename: Gabriella
authors.initials: G
authors.lastname: Gentile
authors.forename: Giovanni
authors.initials: G
authors.lastname: Bernasconi
authors.forename: Alfonso
authors.initials: A
authors.lastname: Pozzan
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Merlo
authors.forename: Paola
authors.initials: P
authors.lastname: Marzorati
authors.forename: Paul
authors.initials: P
authors.lastname: Bamborough
authors.forename: Benjamin
authors.initials: B
authors.lastname: Bax
authors.forename: Angela
authors.initials: A
authors.lastname: Bridges
authors.forename: Caroline
authors.initials: C
authors.lastname: Brough
authors.forename: Paul
authors.initials: P
authors.lastname: Carter
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Cutler
authors.forename: Margarete
authors.initials: M
authors.lastname: Neu
authors.forename: Mia
authors.initials: M
authors.lastname: Takada
mesh_terms: D002460:Cell Line; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D010539:Permeability / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D047428:Protein Kinase Inhibitors; D011728:Pyridones; D013876:Thiophenes; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3