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

doi:10.1016/j.ejmech.2019.07.032

	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
	Wang, Yibing 1,2,3; Lou, Yang 2,3; Wang, Jiang 1,2,3; Li, Dan 2,3; Chen, Hui 2,3; Zheng, Tiannan 1,2,3; Xia, Chunmei 2,3; Song, Xiaohan 1,2,3; Dong, Tiancheng 2,3; Li, Jingya 1,2,3
刊名	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
	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
DOI	10.1016/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.
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关键词	CARDIOVASCULAR OUTCOMES ; DOUBLE-BLIND ; DUAL SGLT1 ; DISCOVERY ; POTENT ; CANAGLIFLOZIN ; EMPAGLIFLOZIN ; INSULIN ; LUSEOGLIFLOZIN ; SOTAGLIFLOZIN
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
WOS记录号	WOS:000488307100031
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/282687]
专题	中国科学院上海药物研究所
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.