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].
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.