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.

参考文献:
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.