APD668

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.

APD668, a G protein-coupled receptor 119 agonist improves fat tolerance and attenuates fatty liver in high-trans fat diet induced steatohepatitis model in C57BL/6 mice.[Pubmed:28274625]

Eur J Pharmacol. 2017 Apr 15;801:35-45.

G-protein coupled receptor 119 (GPR119) receptor is a rhodopsin-like, class A Galphas-coupled receptor, predominantly expressed in pancreatic islet cells and intestinal entero-endocrine cells. GPR119 has been emerged as a novel therapeutic target for the treatment of dyslipidemia in type 2 diabetes. In this study, we investigated the effect of APD668, a GPR119 agonist alone and in combination with linagliptin, a DPPIV inhibitor on oral fat tolerance test. Our findings demonstrate that APD668, a GPR119 agonist inhibits the intestinal triglyceride absorption after acute fat load in mice. Single dose administration of APD668 increases incretin secretion and enhances total PYY levels in presence of fat load in mice. We found that, the anti-dyslipidemic action of APD668 was reversed in presence of exendin-3 in oral fat tolerance test. In addition, our results showed that exendin-3 (9-39) failed to block the effect of APD668 on gastric emptying indicating that gastric emptying effects of APD668 are indeed mediated through GPR119 receptor dependent mechanism. Combined administration of APD668 and linagliptin significantly increased plasma active GLP-1 levels in-vivo and showed improvement in fat tolerance. However, APD668 failed to show anti-dyslipidemic activity in tyloxapol-induced hyperlipidemia in mice. Furthermore, we investigated the chronic effects of APD668 on hepatic steatosis in high trans-fat diet fed steatohepatitis model in mice. Oral administration of APD668 in HTF diet fed mice ameliorated hepatic endpoints such as plasma ALT, AST, liver weight and steatosis. These findings suggest that GPR119 agonists may represent a promising therapeutic strategy for the treatment of dyslipidemia and non-alcoholic steatohepatitis.