GSK1292263

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Background

GSK1292263 is a novel agonist of GPR119 receptor agonist and is used for the treatment of type 2 diabetes. GPR119 is described as a class A (rhodopsin-type) orphan GPCR with no close primary sequence relative in the human genome. The activation of GPR119 increases the intracellular accumulation of cAMP, resulting in enhanced insulin secretion from pancreatic β-cells and increased release of the gut peptides GLP-1 (glucagon-like peptide 1), GIP (glucose-dependent insulinotropic peptide) and PYY (polypeptide YY). In vitro, GSK1292263 treatment displayed little inhibition towards CYPs (CYP1A2, 2C9, 2C19, 2D6, 3A4), p-GP, OATP1B3, or OCT2. However, GSK1292263 inhibited BCRP and OATP1B1, which are transporters involved in statin disposition 1. In the glucose tolerance test in rats, administration of GSK-1292263 significantly increases the peak insulin response and insulin AUC (0-15 min) as compared with the values in the vehicle control. The upregulation of insulin was found to correlate with an increase in the glucose disposal rate. In hyperinsulinemic-euglycemic clamps, GSK-1292263 administration on Sprague-Dawley rats at dose of 10 or 30 mg/kg 2 hours prior to insulin infusion can promote glucagon secretion with no increase of blood glucose levels 2.

1. Polli JW, Hussey E, Bush M, et al. Evaluation of drug interactions of GSK1292263 (a GPR119 agonist) with statins: from in vitro data to clinical study design. Xenobiotica; the fate of foreign compounds in biological systems. 2013;43(6):498-508.
2. Zhu X, Huang D, Lan X, et al. The first pharmacophore model for potent G protein-coupled receptor 119 agonist. European journal of medicinal chemistry. 2011;46(7):2901-2907.