State Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China.
State Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203, China.
Eur J Med Chem. 2019 Oct 15;180:398-416. doi: 10.1016/j.ejmech.2019.07.032. Epub 2019 Jul 10.
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 (IC = 4.5 nM), good pharmacokinetic profiles, and more remarkable efficacy in C57BL/6J mice and Sprague-Dawley rats than marketed drug tofogliflozin.
在这项工作中，我们旨在寻找一种新型、有效且选择性高的钠依赖性葡萄糖共转运蛋白 2（SGLT2）抑制剂，具有良好的药代动力学特性，用于治疗糖尿病。我们专注于修饰 SGLT2 抑制剂的糖部分，通过去除 C-6 羟基来调节 SGLT2 抑制剂的理化性质和靶标识别方式，该部分在与 hSGLT 的葡萄糖结合位点结合中起主导作用。此外，含有特殊 O-螺缩酮 C-芳基葡糖苷骨架的托格列净在动物和人体中均显示出良好的疗效和生物利用度。因此，本工作设计、合成并评价了一系列 6-去氧 O-螺缩酮 C-芳基葡糖苷作为新型 SGLT2 抑制剂。对这一系列新型化合物的构效关系（SAR）研究以及全面的体外和体内生物学评价，得到了具有高体外 hSGLT2 抑制活性（IC=4.5nM）、良好药代动力学特性的化合物 39，并且在 C57BL/6J 小鼠和 Sprague-Dawley 大鼠中的疗效优于市售药物托格列净。
