title: Discovery of new nanomolar inhibitors of GPa: Extension of 2-oxo-1,2-dihydropyridinyl-3-yl amide-based GPa inhibitors.
abstract: Glycogen Phosphorylase (GP) is a functionally active dimeric enzyme, which is a target for inhibition of the conversion of glycogen to glucose-1-phosphate. In this study we report the design and synthesis of 14 new pyridone derivatives, and seek to extend the SAR analysis of these compounds. The SAR revealed the minor influence of the amide group, importance of the pyridone ring both spatially around the pyridine ring and for possible π-stacking, and confirmed a preference for inclusion of 3,4-dichlorobenzyl moieties, as bookends to the pyridone scaffold. Upon exploring a dimer strategy as part of the SAR analysis, the first extended 2-oxo-dihydropyridinyl-3-yl amide nanomolar based inhibitors of GPa (IC50= 230 and 260 nM) were identified.
authors.affiliation: School of Natural Sciences, Griffith University, Brisbane, Qld, 4111, Australia. Electronic address: w.loughlin@griffith.edu.au.
authors.forename: Wendy A
authors.initials: WA
authors.lastname: Loughlin
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University, Brisbane, Qld, 4111, Australia.
authors.forename: Ian D
authors.initials: ID
authors.lastname: Jenkins
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University, Brisbane, Qld, 4111, Australia.
authors.forename: N David
authors.initials: ND
authors.lastname: Karis
authors.affiliation: School of Natural Sciences, Griffith University, Brisbane, Qld, 4111, Australia; Central Analytical Research Facility, Queensland University of Technology, Brisbane, Qld, 4001, Australia.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Healy
mesh_terms: D000577:Amides / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D024981:Glycogen Phosphorylase / Q000037:antagonists & inhibitors*; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D008968:Molecular Conformation; D011817:Rabbits
chemical_list: D000577:Amides; D004791:Enzyme Inhibitors; D024981:Glycogen Phosphorylase
keywords: Dimer; Glycogen phosphorylase inhibitors; Pyridone amides; Structure activity relationship; Type 2 diabetes