title: N-Phenyl-4-pyrazolo[1,5-b]pyridazin-3-ylpyrimidin-2-amines as potent and selective inhibitors of glycogen synthase kinase 3 with good cellular efficacy.
abstract: Glycogen synthase kinase 3 regulates glycogen synthase, the rate-determining enzyme for glycogen synthesis. Liver and muscle glycogen synthesis is defective in type 2 diabetics, resulting in elevated plasma glucose levels. Inhibition of GSK-3 could potentially be an effective method to control plasma glucose levels in type 2 diabetics. Structure-activity studies on a N-phenyl-4-pyrazolo[1,5-b]pyridazin-3-ylpyrimidin-2-amine series have led to the identification of potent and selective compounds with good cellular efficacy. Molecular modeling studies have given insights into the mode of binding of these inhibitors. Since the initial leads were also potent inhibitors of CDK-2/CDK-4, an extensive SAR was performed at various positions of the pyrazolo[1,5-b]pyridazin core to afford potent GSK-3 inhibitors that were highly selective over CDK-2. In addition, these inhibitors also exhibited very good cell efficacy and functional response. A representative example was shown to have good oral exposure levels, extending their utility in an in vivo setting. These inhibitors provide a viable lead series in the discovery of new therapies for the treatment of type 2 diabetes.
authors.affiliation: Department of Medicinal Chemistry, GlaxoSmithKline, Research Triangle Park, North Carolina 27709, USA. fxt66911@gsk.com
authors.forename: Francis X
authors.initials: FX
authors.lastname: Tavares
authors.forename: Joyce A
authors.initials: JA
authors.lastname: Boucheron
authors.forename: Scott H
authors.initials: SH
authors.lastname: Dickerson
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Griffin
authors.forename: Frank
authors.initials: F
authors.lastname: Preugschat
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Thomson
authors.forename: Tony Y
authors.initials: TY
authors.lastname: Wang
authors.forename: Hui-Qiang
authors.initials: HQ
authors.lastname: Zhou
mesh_terms: D000588:Amines / Q000737:chemistry*; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D017434:Protein Structure, Tertiary; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000588:Amines; D004791:Enzyme Inhibitors; D011724:Pyridazines; C062482:pyridazine; D038362:Glycogen Synthase Kinase 3