DS-8500a, an orally available G protein-coupled receptor 119 agonist, upregulates glucagon-like peptide-1 and enhances glucose-dependent insulin secretion and improves glucose homeostasis in type 2 diabetic rats.

G protein-coupled receptor 119 (GPR119) has been shown to be highly expressed in small intestinal L-cells and pancreatic β-cells and mediates intracellular cyclic adenosine monophosphate (cAMP) concentration, glucagon like peptide (GLP-1) secretion, and glucose-stimulated insulin secretion (GSIS). This study examined the pharmacological effects of 4-(5-{(1R)-1-[4-(Cyclopropylcarbonyl) phenoxy]propyl}-1,2,4-oxadiazol-3-yl)-2-fluoro-N-[(2R)-1-hydroxypropan-2-yl]benzamide (DS-8500a), a novel, orally available, selective GPR119 agonist. In in vitro studies, DS-8500a increased intracellular cAMP in human, rat, and mouse GPR119 expressing Chinese hamster ovary (CHO)-K1 cells in a concentration-dependent manner, and their 50% effective concentrations (EC50) were 51.5, 98.4, and 108.1 nmol/L, respectively. DS-8500a had no effect on intracellular cAMP in pcDNA3.1/CHO-K1 cells. In in vivo studies, DS-8500a augmented plasma GLP-1 concentration in Zucker fatty (ZF) rats, and enhanced GSIS and did not change plasma glucose concentration in fasted Sprague Dawley (SD) rats. The plasma glucose lowering effects of DS-8500a at oral glucose tolerance test (OGTT) were demonstrated in ZF rats and neonatal streptozotpcin (nSTZ) induced diabetic rats. Single dose of DS-8500a showed dose dependent glucose lowering effects at OGTT in ZF rats. In the repeat dosing study, DS-8500a had statistically significant glucose lowering effects at OGTT performed at the first day and after 2-weeks treatment in nSTZ rats, and the efficacy levels of DS-8500a in each test were greater than those of GSK1292263 or MBX-2982 which had been clinically tested GPR119 agonists.