GSK1292263

Uses

GSK-1292263 is an orally available GPR119 agonist with pEC50s of 6.9 and 6.7 for human and rat GPR119, respectively. GSK-1292263 can be used for the research of type 2 diabetes mellitus (T2DM)[1].

Biological Activity

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.

Synthesis

1032825-19-6

1032825-20-9

1032823-75-8

1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinylmethyl methanesulfonate (82.3 g, 271 mmol) and 5-hydroxy-2-(4-methylsulfonylphenyl)pyridine (71.0 g, 285 mmol) were added with powdered potassium carbonate (118 g, 855 mmol) and N,N-dimethylformamide ( 750 mL), and the reaction was mechanically stirred at 80 °C for 20 h under nitrogen protection. After completion of the reaction, it was cooled to room temperature, poured into ice water (3 L) and left to stand for 1 hour. The solid product was collected by filtration, washed with water (2 x 500 mL) and air dried. The dried solid was dissolved in a solvent mixture of dichloromethane (300 mL) and methanol (500 mL). The dichloromethane was slowly evaporated by rotary evaporator at 55°C. The remaining methanol solution was allowed to stand at room temperature for 16 hours to induce crystallization. The crystalline solid was obtained by filtration, washed with cold methanol and dried under vacuum at 60 °C for 18 h. The target compound 3-isopropyl-5-(4-(((6-(4-(4-(methylsulfonyl)phenyl)pyridin-3-yl)oxy)methyl)piperidin-1-yl)-1,2,4-oxadiazole (105.7 g, 84% yield) was obtained as a light tan solid.1H NMR (400 MHz. CDCl3): δ 8.41 (d, 1H, J=2.8 Hz), 8.13 (d, 2H, J=8.6 Hz), 8.01 (d, 2H, J=8.6 Hz), 7.74 (d, 1H, J=8.7 Hz), 7.29 (dd, 1H, Ja=8.7 Hz, Jb=3.0 Hz), 4.24 (d, 2H, J=13.1 Hz), 3.95 (d, 2H, J=6.2 Hz), 3.17-3.04 (m, 5H), 2.94-2.84 (m, 1H), 2.11 (bs, 1H), 1.97 (d, 2H, J=12.6 Hz), 1.54-1.42 (m, 2H), 1.29 (d, 6H, J=7.0 Hz); LRMS (ESI ), m/z 457 (M+H).

in vivo

target

GPR119

References

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.