title: Novel GSK-3 inhibitors with improved cellular activity.
abstract: A novel series of [1-(1H-benzimidazol-7-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl] arylhydrazones was synthesized and shown to potently inhibit glycogen synthase kinase-3 (GSK-3). In light of detailed structure-activity relationships and structural knowledge of the GSK-3 binding pocket, a benzimidazole substituent was incorporated onto the pyrazolopyrimidine core resulting in improved potency over previous analogs. More importantly, these derivatives show low nanomolar efficacy for stimulating glycogen synthesis in vitro and therefore may be useful in the treatment of type 2 diabetes mellitus.
authors.affiliation: GlaxoSmithKline Research and Development, 5 Moore Drive, Research Triangle Park, NC 27709, USA. ajp25551@gsk.com
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Peat
authors.forename: Dulce
authors.initials: D
authors.lastname: Garrido
authors.forename: Joyce A
authors.initials: JA
authors.lastname: Boucheron
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Schweiker
authors.forename: Scott H
authors.initials: SH
authors.lastname: Dickerson
authors.forename: Jayme R
authors.initials: JR
authors.lastname: Wilson
authors.forename: Tony Y
authors.initials: TY
authors.lastname: Wang
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Thomson
mesh_terms: D000818:Animals; D002460:Cell Line; D004285:Dogs; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D006835:Hydrazones / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular
chemical_list: D004791:Enzyme Inhibitors; D006835:Hydrazones; D038362:Glycogen Synthase Kinase 3