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 Feb 1;29(3):373-379. doi: 10.1016/j.bmcl.2018.12.041. Epub 2018 Dec 18.
We describe here the generation of a lead compound and its optimization studies that led to the identification of a novel GPR119 agonist. Based on a spirocyclic cyclohexane structure reported in our previous work, we identified compound 8 as a lead compound, being guided by ligand-lipophilicity efficiency (LLE), which linked potency and lipophilicity. Subsequent optimization studies of 8 for improvement of solubility afforded representative 21. Compound 21 had no inhibitory activity against six CYP isoforms and showed favorable pharmacokinetic properties and hypoglycemic activity in rats.
我们在此描述了一种先导化合物的生成及其优化研究，该研究导致了一种新型 GPR119 激动剂的发现。基于我们之前工作中报道的螺环环己烷结构，我们确定化合物 8 为先导化合物，这是由配体脂溶性效率 (LLE) 指导的，它将效力和脂溶性联系起来。随后对 8 进行了溶解度方面的优化研究，得到了具有代表性的 21 号化合物。化合物 21 对六种 CYP 同工酶没有抑制活性，并且在大鼠中表现出良好的药代动力学特性和降血糖活性。
