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Design, synthesis and biological evaluation of 6-deoxy O-spiroketal C-arylglucosides as novel renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors for the treatment of type 2 diabetes

文献类型：期刊论文

作者Wang, Yibing1,2,3; Lou, Yang2,3; Wang, Jiang1,2,3; Li, Dan2,3; Chen, Hui2,3; Zheng, Tiannan1,2,3; Xia, Chunmei2,3; Song, Xiaohan1,2,3; Dong, Tiancheng2,3; Li, Jingya1,2,3
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2019-10-15
卷号180页码:398-416
关键词SGLT2 inhibitors Diabetes Sugar modification Structure-activity relationship Urinary glucose excretion Oral glucose tolerance
ISSN号0223-5234
DOI10.1016/j.ejmech.2019.07.032
通讯作者Li, Jia(jli@simm.ac.cn) ; Liu, Hong(hliu@simm.ac.cn)
英文摘要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. (C) 2019 Elsevier Masson SAS. All rights reserved.
WOS关键词CARDIOVASCULAR OUTCOMES ; DOUBLE-BLIND ; DUAL SGLT1 ; DISCOVERY ; POTENT ; CANAGLIFLOZIN ; EMPAGLIFLOZIN ; INSULIN ; LUSEOGLIFLOZIN ; SOTAGLIFLOZIN
资助项目National Program on Key Basic Research Project of China[2015CB910304] ; National Natural Science Foundation[81620108027] ; National Natural Science Foundation[21632008] ; National Natural Science Foundation[21402226] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12040201] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program[2018ZX09711002-012-006] ; Shanghai Science and Technology Development Fund[17431903100]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000488307100031
出版者ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
源URL[http://119.78.100.183/handle/2S10ELR8/282687]  
专题新药研究国家重点实验室
通讯作者Li, Jia; Liu, Hong
作者单位1.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Materia Med, State Key Lab Drug Res, 555 Chong Zhi Rd, Shanghai 201203, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Materia Med, CAS Key Lab Receptor Res, 555 Chong Zhi Rd, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Wang, Yibing,Lou, Yang,Wang, Jiang,et al. Design, synthesis and biological evaluation of 6-deoxy O-spiroketal C-arylglucosides as novel renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors for the treatment of type 2 diabetes[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2019,180:398-416.
APA Wang, Yibing.,Lou, Yang.,Wang, Jiang.,Li, Dan.,Chen, Hui.,...&Liu, Hong.(2019).Design, synthesis and biological evaluation of 6-deoxy O-spiroketal C-arylglucosides as novel renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors for the treatment of type 2 diabetes.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,180,398-416.
MLA Wang, Yibing,et al."Design, synthesis and biological evaluation of 6-deoxy O-spiroketal C-arylglucosides as novel renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors for the treatment of type 2 diabetes".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 180(2019):398-416.

入库方式： OAI收割

来源：上海药物研究所

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