title: Glycogen phosphorylase inhibitory effects of 2-oxo-1,2-dihydropyridin-3-yl amide derivatives.
abstract: Glycogen phosphorylase (GP) plays a crucial role in the conversion of glycogen to glucose-1-phosphate (and in turn glucose) and is a promising target for therapeutic intervention in diabetes. In this study we synthesized new derivatives of 2-oxo-1,2-dihydropyridin-3-yl amides using a facile aminolysis reaction, in which different alkyl and aryl esters and amides are substituted at N-1 and C-3 of the heterocyclic ring. The in vitro inhibitory activity of compounds against glycogen phosphorylase was evaluated. From this series the most potent compound exhibits good GPa inhibition (IC(50)=6.3 microM). A preliminary study of these compounds showed that anti-GP activity was decreased by the incorporation of a C3-N carbonyl group and favored by increased lipophilicity.
authors.affiliation: Eskitis Institute for Cell and Molecular Therapies, Griffith University, Brisbane, QLD, Australia.
authors.forename: N David
authors.initials: ND
authors.lastname: Karis
authors.forename: Wendy A
authors.initials: WA
authors.lastname: Loughlin
authors.forename: Ian D
authors.initials: ID
authors.lastname: Jenkins
authors.forename: Peter C
authors.initials: PC
authors.lastname: Healy
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000595:Amino Acid Sequence; D000818:Animals; D018360:Crystallography, X-Ray; D024981:Glycogen Phosphorylase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009132:Muscles / Q000201:enzymology; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D016415:Sequence Alignment; D013329:Structure-Activity Relationship
chemical_list: C543315:2-(3'-(benzylamino)-2'-oxopyridin-1'(2H)-yl)-N-(3'',4''-dichlorobenzyl)acetamide; D000577:Amides; D011728:Pyridones; D024981:Glycogen Phosphorylase