Uses
APD 668 is a potent agonist of GPR119, a glucose-dependant insulinotropic receptor expressed in pancreatic β-cells and intestinal L-cells.
Biological Activity
apd688 is a selective and potent g protein-coupled receptor 119 (gpr119) agonist with an ec50 value of 2.7 nm for hgpr119 and 33 nm for rgpr119, and showed a moderate inhibition of the herg channel (ic50 = 3 ?m), exhibiting an in vivo activity of glucose regulation in rodent models [1].gpr199, which is predominantly expressed in human and rodent pancreas, is a membrane receptor that plays a role in the production of insulin as a response to high glucose concentration in male wistar rats, and is a probable target for the treatment of diabetes [2]. gpr199 is also localized in the gastrointestinal track, providing a potential target for obesity therapy and other related metabolic disorders through reduced food intake [3].in hek293 cells transfected with human gpr119, application of apd688 displayed an increase in adenylatecyclase activation subsequently leading to enhanced release of insulin in a glucose-dependent manner [1].oral administration of apd688 in zucker diabetic fatty (zdf) rats for over 8 weeks resulted in the significant decrease in blood glucose and glycated hemoglobin (hba1c) levels. in addition, the compound is mostly non-genotoxic, and shows no significant inhibition of cyp isoforms except for cyp2c9 (ki = 0.1 ?m) in human hepatic microsomes [1].
in vivo
APD668 (10-30 mg/kg; p.o. once daily for 8 weeks) significantly reduces blood glucose and glycated hemoglobin (HbA1c) levels, with no desensitization of the acute drug response[1].
APD668 (1-10 mg/kg; a single p.o.) markedly reduces blood glucose levels during oral glucose tolerance test in a dose-dependent manner in mice[1].
APD668 (0.08 mg/kg/min; i.v.) shows no effect during euglycemic condition, but significantly stimulates insulin release when blood glucose levels are raised to approximately 300 mg/dl in a hyperglycemic clamp model in the Sprague-Dawley rat[1].
APD668 (p.o.) exhibits rapid to moderate absorption (tmax≤2 h) in mice, rats, and monkeys, but slower in dogs (tmax=6 h), and moderate to good absolute oral bioavailability (44-79%) in mice, rats, and monkeys, but lower in dogs (22%)[1].
| Animal Model: | Male Zucker Diabetic Fatty (ZDF) rats (6 weeks old, 200-250 g)[1] |
| Dosage: | 10, 30 mg/kg |
| Administration: | P.o. once daily for 8 weeks |
| Result: | Decreased the blood glucose and HbA1c levels at 30 mg/kg/day.
Did not develop diabetes, whereas the vehicle treated rats did.
|
IC 50
hGPR119: 2.7 nM (IC50); rGPR119: 33 nM (IC50); CYP2C9: 0.1 μM (Ki); hERG channel: 3 μM (IC50)
References
[1]. semple g, ren a, fioravanti b, et al. discovery of fused bicyclic agonists of the orphan g-protein coupled receptor gpr119 with in vivo activity in rodent models of glucose control. bioorg med chem lett, 2011, 21(10):3134-41.
[2]. soga t, ohishi t, matsui t, et al. lysophosphatidylcholine enhances glucose-dependent insulin secretion via an orphan g-protein-coupled receptor. biochem biophys res commun, 2005, 326(4):744-51.
[3]. overton ha, babbs aj, doel sm, et al. deorphanization of a g protein coupled receptor for oleoylethanolamide and its use in the discovery of small molecule hypophagic agents. cell metab, 2006, 3(3):167-75.
