化学
生物利用度
体内
达帕格列嗪
药代动力学
协同运输机
药理学
体外
IC50型
卡格列净
部分
恩帕吉菲
生物化学
内科学
肾葡萄糖重吸收
运输机
钠
根皮苷
2型糖尿病
内分泌学
胰岛素
葡萄糖转运蛋白
立体化学
糖尿病
有机化学
生物技术
生物
医学
作者
Yibing Wang,Yang Lou,Jiang Wang,Dan Li,H. S. Chen,Tian-nan Zheng,Chunmei Xia,Xiaohan Song,Tiancheng Dong,Jia Li,Jia Li,Hong Liu
标识
DOI:10.1016/j.ejmech.2019.07.032
摘要
In this work, aiming at finding a novel, potent, and selective sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor with good pharmacokinetic profiles for the treatment of diabetes, we focus on modifying the sugar moiety of SGLT2 inhibitors, which dominates the binding with glucose binding site of hSGLT, via removing the C-6 hydroxy group to adjust the physicochemical properties and target-recognition manners of SGLT2 inhibitors. In addition, tofogliflozin containing a special O-spiroketal C-arylglucoside scaffold, displayed good efficacy and bioavailability both in animals and in humans. Therefore, a series of 6-deoxy O-spiroketal C-arylglucosides as novel SGLT2 inhibitors were designed, synthesized, and evaluated in this work. The structure-activity relationship (SAR) research on this novel series and a comprehensive in vitro and in vivo biological evaluation afforded compound 39 with high in vitro hSGLT2 inhibitory activity (IC50 = 4.5 nM), good pharmacokinetic profiles, and more remarkable efficacy in C57BL/6J mice and Sprague-Dawley rats than marketed drug tofogliflozin.
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