Shen Hong C, Ding Fa-Xiang, Deng Qiaolin, Wilsie Larissa C, Krsmanovic Mihajlo L, Taggart Andrew K, Carballo-Jane Ester, Ren Ning, Cai Tian-Quan, Wu Tsuei-Ju, Wu Kenneth K, Cheng Kang, Chen Qing, Wolff Michael S, Tong Xinchun, Holt Tom G, Waters M Gerard, Hammond Milton L, Tata James R, Colletti Steven L
Departments of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., Rahway, New Jersey 07065-0900, USA.
J Med Chem. 2009 Apr 23;52(8):2587-602. doi: 10.1021/jm900151e.
Tricyclic analogues were rationally designed as the high affinity niacin receptor G-protein-coupled receptor 109A (GPR109A) agonists by overlapping three lead structures. Various tricyclic anthranilide and cycloalkene carboxylic acid full agonists were discovered with excellent in vitro activity. Compound 2g displayed a good therapeutic index regarding free fatty acids (FFA) reduction and vasodilation effects in rats, with very weak cytochrome P450 2C8 (CYP2C8) and cytochrome P450 2C9 (CYP2C9) inhibition, and a good mouse pharmacokinetics (PK) profile.
通过重叠三种先导结构，合理设计了三环类似物作为高亲和力烟酸受体G蛋白偶联受体109A（GPR109A）激动剂。发现了各种三环邻氨基苯甲酰和环烯烃羧酸完全激动剂，具有优异的体外活性。化合物2g在降低大鼠游离脂肪酸（FFA）和血管舒张作用方面显示出良好的治疗指数，对细胞色素P450 2C8（CYP2C8）和细胞色素P450 2C9（CYP2C9）的抑制作用非常弱，并且具有良好的小鼠药代动力学（PK）特征。
