Intestinally-targeted TGR5 agonists equipped with quaternary ammonium have an improved hypoglycemic effect and reduced gallbladder filling effect

doi:10.1038/srep28676

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药理学第一研究室

	Intestinally-targeted TGR5 agonists equipped with quaternary ammonium have an improved hypoglycemic effect and reduced gallbladder filling effect
	Cao, Hua 1; Chen, Zhi-Xiang 1,2; Wang, Kai 1; Ning, Meng-Meng1 ; Zou, Qing-An 1; Feng, Ying 1; Ye, Yang-Liang1 ; Leng, Ying1 ; Shen, Jian-Hua1
刊名	SCIENTIFIC REPORTS
	2016-06-24
卷号	6
ISSN号	2045-2322
DOI	10.1038/srep28676
文献子类	Article
英文摘要	TGR5 activation of enteroendocrine cells increases glucagon-like peptide 1 (GLP-1) release, which maintains glycemic homeostasis. However, TGR5 activation in the gallbladder and heart is associated with severe side effects. Therefore, intestinally-targeted TGR5 agonists were suggested as potential hypoglycemic agents with minimal side effects. However, until now no such compounds with robust glucose-lowering effects were reported, especially in diabetic animal models. Herein, we identify a TGR5 agonist, 26a, which was proven to be intestinally-targeted through pharmacokinetic studies. 26a was used as a tool drug to verify the intestinally-targeted strategy. 26a displayed a robust and long-lasting hypoglycemic effect in ob/ob mice (once a day dosing (QD) and 18-day treatment) owing to sustained stimulation of GLP-1 secretion, which suggested that robust hypoglycemic effect could be achieved with activation of TGR5 in intestine alone. However, the gallbladder filling effect of 26a was rather complicated. Although the gallbladder filling effect of 26a was decreased in mice after once a day dosing, this side effect was still not eliminated. To solve the problem above, several research strategies were raised for further optimization.
资助项目	National Nature Science Foundation of China[81473093] ; State Key Laboratory of Drug Research[SIMM1403ZZ-03] ; Shanghai Institute of Materia Medica[CASIMM0120152030]
WOS关键词	BILE-ACID RECEPTOR ; POTENT ; DISCOVERY ; IDENTIFICATION ; OPTIMIZATION ; SEQUESTRANTS ; MECHANISMS ; SECRETION ; EFFICACY
WOS研究方向	Science & Technology - Other Topics
语种	英语
出版者	NATURE PUBLISHING GROUP
WOS记录号	WOS:000378415100001
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/275987]
专题	药理学第一研究室中科院受体结构与功能重点实验室新药研究国家重点实验室药物发现与设计中心
通讯作者	Leng, Ying; Shen, Jian-Hua
作者单位	1.Chinese Acad Sci, SIMM, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 2.Nanchang Univ, Coll Pharm, Nanchang 330006, Peoples R China
推荐引用方式 GB/T 7714	Cao, Hua,Chen, Zhi-Xiang,Wang, Kai,et al. Intestinally-targeted TGR5 agonists equipped with quaternary ammonium have an improved hypoglycemic effect and reduced gallbladder filling effect[J]. SCIENTIFIC REPORTS,2016,6.
APA	Cao, Hua.,Chen, Zhi-Xiang.,Wang, Kai.,Ning, Meng-Meng.,Zou, Qing-An.,...&Shen, Jian-Hua.(2016).Intestinally-targeted TGR5 agonists equipped with quaternary ammonium have an improved hypoglycemic effect and reduced gallbladder filling effect.SCIENTIFIC REPORTS,6.
MLA	Cao, Hua,et al."Intestinally-targeted TGR5 agonists equipped with quaternary ammonium have an improved hypoglycemic effect and reduced gallbladder filling effect".SCIENTIFIC REPORTS 6(2016).