title: 2-Oxo-1,2-dihydropyridinyl-3-yl amide-based GPa inhibitors: Design, synthesis and structure-activity relationship study.
abstract: Glycogen phosphorylase (GP), which plays a crucial role in the conversion of glycogen to glucose-1-phosphate, is a target for therapeutic intervention in diabetes. In this study, we report the design and synthesis of 29 new derivatives of 2-oxo-1,2-dihydro pyridin-3-yl amides, as potential inhibitors of GP. The hit rate (45%) was high with 13 compounds inhibiting GPa (between 33% at 4.40 mM and an IC50 of 1.92 μM). Two lead compounds were identified as compounds exhibiting good GPa inhibition (IC50 = 2.1 and 1.92 μM). SAR analysis of these compounds revealed sensitivity of GPa to the length of the 2-oxo-1,2-dihydro pyridin-3-yl amide derivative and a preference for inclusion of a 3,4-dichlorobenzyl moiety.
authors: School of Natural Sciences, Griffith University, Brisbane, QLD, 4111, Australia. Electronic address: w.loughlin@griffith.edu.au.
authors: Wendy A
authors: WA
authors: Loughlin
authors: Eskitis Institute for Drug Discovery, Griffith University, Brisbane, QLD, 4111, Australia.
authors: Ian D
authors: ID
authors: Jenkins
authors: Eskitis Institute for Drug Discovery, Griffith University, Brisbane, QLD, 4111, Australia.
authors: N David
authors: ND
authors: Karis
authors: Eskitis Institute for Drug Discovery, Griffith University, Brisbane, QLD, 4111, Australia.
authors: Stephanie S
authors: SS
authors: Schweiker
authors: School of Natural Sciences, Griffith University, Brisbane, QLD, 4111, Australia; Central Analytical Research Facility, Queensland University of Technology, Brisbane, QLD, 4001, Australia.
authors: Peter C
authors: PC
authors: Healy
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D024981:Glycogen Phosphorylase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000081:Acetamides; D004791:Enzyme Inhibitors; D011728:Pyridones; D024981:Glycogen Phosphorylase
keywords: Glycogen phosphorylase inhibitors; Peptide mimetic; Pyridone amides; Structure activity relationship; Type 2 diabetes