Amino acid anthranilamide derivatives as a new class of glycogen phosphorylase inhibitors |
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| Authors: | Evans Karen A Li Yue H Coppo Frank T Graybill Todd L Cichy-Knight Maria Patel Mehul Gale Jennifer Li Hu Thrall Sara H Tew David Tavares Francis Thomson Stephen A Weiel James E Boucheron Joyce A Clancy Daphne C Epperly Andrea H Golden Pamela L |
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| Institution: | aDiscovery Research, GlaxoSmithKline Pharmaceuticals, 1250 South Collegeville Road, PO Box 5089, Collegeville, PA 19426-0989, USA;bMetabolic and Viral Diseases Center of Excellence for Drug Discovery, GlaxoSmithKline Pharmaceuticals, Five Moore Drive, PO Box 13398, Research Triangle Park, NC 27709-3398, USA |
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| Abstract: | A series of amino acid anthranilamide derivatives identified from a high-throughput screening campaign as novel, potent, and glucose-sensitive inhibitors of human liver glycogen phosphorylase a are described. A solid-phase synthesis using Wang resin was also developed which provided efficient access to a variety of analogues, and resulted in the identification of key structure–activity relationships, and the discovery of a potent exemplar (IC50 = 80 nM). The SAR scope, synthetic strategy, and in vitro results for this series are presented herein. |
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| Keywords: | Human liver glycogen phosphorylase Glycogen phosphorylase inhibitors Solid-phase synthesis |
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