2-Oxo-1,2-dihydropyridinyl-3-yl amide-based GPa inhibitors: Design, synthesis and structure-activity relationship study

Wendy A. Loughlin, Ian D. Jenkins, N. David Karis, Stephanie S. Schweiker, Peter C. Healy

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3 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1-14
Number of pages14
JournalEuropean Journal of Medicinal Chemistry
Volume111
DOIs
Publication statusPublished - 23 Mar 2016

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Glycogen Phosphorylase
Structure-Activity Relationship
Amides
Inhibitory Concentration 50
Lead compounds
Derivatives
Medical problems
Glycogen
Therapeutics
glucose-1-phosphate
Lead

Cite this

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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.",
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2-Oxo-1,2-dihydropyridinyl-3-yl amide-based GPa inhibitors : Design, synthesis and structure-activity relationship study. / Loughlin, Wendy A.; Jenkins, Ian D.; Karis, N. David; Schweiker, Stephanie S.; Healy, Peter C.

In: European Journal of Medicinal Chemistry, Vol. 111, 23.03.2016, p. 1-14.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Healy, Peter C.

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