Title

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

Date of this Version

3-23-2016

Document Type

Journal Article

Publication Details

Citation only

Loughlin, W. A., Jenkins, I. D., Karis, N. D., Schweiker, S. S., & Healy, P. C. (2016). 2-Oxo-1,2-dihydropyridinyl-3-yl amide-based GPa inhibitors: Design, synthesis and structure-activity relationship study. European Journal of Medicinal Chemistry, 111, 1-14.

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2016 HERDC submission

© Copyright, 2016 Elsevier Masson SAS

ISSN

0223-5234

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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This document has been peer reviewed.