APD668

APD668是高效选择性G蛋白偶联受体119(GPR119)激动剂,对hGPR119和rGPR119的EC50值分别为2.7 nM和33 nM,对hERG通道具有中度的抑制作用(IC50 = 3 μM),在啮齿动物模型中也具有调节葡萄糖的体内效应[1].

GPR119主要表达于人和啮齿动物的胰腺中,其作为一种膜受体,在雄性Wistar大鼠应答高葡糖糖浓度产生胰岛素中发挥重要作用,也是糖尿病治疗的潜在靶点[2].GPR199也定位于胃肠道,通过降低食物摄取,为肥胖症治疗和其他相关代谢疾病的治疗提供了潜在的靶点[3].

在转染人GPR119的HEK293细胞中,给予APD688能够提高腺苷酸环化酶活化,随后以葡萄糖依赖的方式提高胰岛素释放[1].

Zucker糖尿病性脂肪肝(ZDF)大鼠口服APD688超过8周导致血糖和糖化血红蛋白(HbAc1)水平显著降低.此外,此化合物通常不具有遗传毒性,在人肝微粒体中对除CYP2C9 (Ki = 0.1 μM)外的其它CYP异构体无明显抑制作用[1].

参考文献：
[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.