Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
Bioorg Med Chem Lett. 2019 Aug 15;29(16):2100-2106. doi: 10.1016/j.bmcl.2019.07.004. Epub 2019 Jul 3.
We describe here a novel GPR119 agonist 24, which showed a potent and long-acting hypoglycemic effect in rats via oral dosing. For the discovery of 24, we chose compound 5, which possessed an oxadiazole linker, as a lead compound among our spirocyclic cyclohexane GPR119 agonist series, taking into account its lower plasma protein binding nature. 3,5-Difluoro and 4-methylsulfonylmethy groups on the left side phenyl group, and a gem-difluoro group on the right side of 24 are important for its agonist potency and metabolic stability, respectively.
我们在这里描述了一种新型的 GPR119 激动剂 24，它通过口服给药在大鼠中显示出强大且长效的降血糖作用。为了发现 24，我们选择了具有噁二唑连接基的化合物 5，作为我们的螺环环己烷 GPR119 激动剂系列中的先导化合物，考虑到其较低的血浆蛋白结合性质。24 左侧苯环上的 3,5-二氟和 4-甲磺酰基甲基基团，以及右侧的偕二氟基团，分别对其激动剂效力和代谢稳定性很重要。
