title: Synthesis and SAR of Benzisothiazole- and Indolizine-β-d-glucopyranoside Inhibitors of SGLT2.
abstract: A series of benzisothiazole- and indolizine-β-d-glucopyranoside inhibitors of human SGLT2 are described. The synthesis of the C-linked heterocyclic glucosides took advantage of a palladium-catalyzed cross-coupling reaction between a glucal boronate and the corresponding bromo heterocycle. The compounds have been evaluated for their human SGLT2 inhibition potential using cell-based functional transporter assays, and their structure-activity relationships have been described. Benzisothiazole-C-glucoside 16d was found to be an inhibitor of SGLT2 with an IC50 of 10 nM.
authors.affiliation: Metabolic Pathways Center of Excellence for Drug Discovery, GlaxoSmithKline, P.O. Box 13398, Research Triangle Park, North Carolina 27709-3398.
authors.forename: Huiqiang
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Metabolic Pathways Center of Excellence for Drug Discovery, GlaxoSmithKline, P.O. Box 13398, Research Triangle Park, North Carolina 27709-3398.
authors.forename: Dana P
authors.initials: DP
authors.lastname: Danger
authors.affiliation: Metabolic Pathways Center of Excellence for Drug Discovery, GlaxoSmithKline, P.O. Box 13398, Research Triangle Park, North Carolina 27709-3398.
authors.forename: Steven T
authors.initials: ST
authors.lastname: Dock
authors.affiliation: Metabolic Pathways Center of Excellence for Drug Discovery, GlaxoSmithKline, P.O. Box 13398, Research Triangle Park, North Carolina 27709-3398.
authors.forename: Lora
authors.initials: L
authors.lastname: Hawley
authors.affiliation: Metabolic Pathways Center of Excellence for Drug Discovery, GlaxoSmithKline, P.O. Box 13398, Research Triangle Park, North Carolina 27709-3398.
authors.forename: Shane G
authors.initials: SG
authors.lastname: Roller
authors.affiliation: Metabolic Pathways Center of Excellence for Drug Discovery, GlaxoSmithKline, P.O. Box 13398, Research Triangle Park, North Carolina 27709-3398.
authors.forename: Chari D
authors.initials: CD
authors.lastname: Smith
authors.affiliation: Metabolic Pathways Center of Excellence for Drug Discovery, GlaxoSmithKline, P.O. Box 13398, Research Triangle Park, North Carolina 27709-3398.
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Handlon
keywords: Benzisothiazole- and indolizine-β-d-glucopyranoside inhibitors; SAR; SGLT2; benzisothiazole-C-glucoside