Discovery and structure-activity relationships study of thieno[2,3-b] pyridine analogues as hepatic gluconeogenesis inhibitors

doi:10.1016/j.ejmech.2018.04.028

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	Discovery and structure-activity relationships study of thieno[2,3-b] pyridine analogues as hepatic gluconeogenesis inhibitors
	Ma, Fei 1,3,5; Liu, Jian 5; Zhou, Tingting 1,4; Lei, Min1,2 ; Chen, Jing1,2 ; Wang, Xiachang 5; Zhang, Yinan 5; Shen, Xu5 ; Hu, Lihong 1,2,5
刊名	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
	2018-05-25
卷号	152 页码:307-317
关键词	Thienol2,3-b]pyridine derivatives Structure-activity relationships (SARs) Hepatic gluconeogenesis Type 2 diabetes mellitus (T2DM)
ISSN号	0223-5234
DOI	10.1016/j.ejmech.2018.04.028
文献子类	Article
英文摘要	Type 2 diabetes mellitus (T2DM) is a chronic, complex and multifactorial metabolic disorder, and targeting gluconeogenesis inhibition is a promising strategy for anti-diabetic drug discovery. This study discovered a new class of thieno[2,3-b]pyridine derivatives as hepatic gluconeogenesis inhibitors. First, a hit compound (DMT: IC50 = 33.8 mu M) characterized by a thienopyridine core was identified in a cell based screening of our privileged small molecule library. Structure activity relationships (SARs) study showed that replaced the CF3 in the thienopyridine core could improve the potency and led to the discovery of 8e (IC50 = 16.8 mu M) and 9d (IC50 = 12.3 mu M) with potent inhibition of hepatic glucose production and good drug-like properties. Furthermore, the mechanism of 8e for the inhibition of hepatic glucose production was also identified, which could be effective through the reductive expression of the mRNA transcription level of gluconeogenic genes, including glucose-6-phosphatase (G6Pase) and hepatic phosphoenolpyruvate carboxykinase (PEPCK). Additionally, 8e could also reduce the fasting blood glucose and improve the oral glucose tolerance and pyruvate tolerance in db/db mice. The optimization of this class of derivatives had provided us a start point to develop new anti-hepatic gluconeogenesis agents. (C) 2018 Elsevier Masson SAS. All rights reserved.
资助项目	National Natural Science Foundation of China[81473110] ; National Natural Science Foundation of China[81773596] ; National Natural Science Foundation of China[81561148011] ; National Natural Science Foundation of China[8170130685] ; Natural Science Foundation of Jiangsu Higher Education Institutions[17KJA360004] ; Natural Science Foundation of Jiangsu Higher Education Institutions[16KJB350003] ; Natural Science Foudation of Jiangsu[SBK2016043296] ; Program of Outstanding Scientific and Technological Innovation Team of Jiangsu Higher Education Institutions[00000000] ; Priority Academic Program Development of Jiangsu Higher Education Institutions[00000000]
WOS关键词	MODULATES GLUCONEOGENESIS ; GLUCOSE-METABOLISM ; METFORMIN ; INSULIN ; HYPERGLYCEMIA ; TRANSCRIPTION ; EFFICACY
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:000435048900025
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279745]
专题	上海中药现代化研究中心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
通讯作者	Shen, Xu; Hu, Lihong
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China; 3.Kansas State Univ, Dept Chem, Manhattan, KS 66506 USA; 4.Jiangnan Univ, Sch Med, Wuxi 214122, Peoples R China 5.Nanjing Univ Chinese Med, Jiangsu Key Lab Funct Subst Chinese Med,Sch Pharm, Jiangsu Collaborat Innovat Ctr Chinese Med Resour, Stake Key Lab Cultivat Base TCM Qual & Efficacy, Nanjing 210023, Jiangsu, Peoples R China;
推荐引用方式 GB/T 7714	Ma, Fei,Liu, Jian,Zhou, Tingting,et al. Discovery and structure-activity relationships study of thieno[2,3-b] pyridine analogues as hepatic gluconeogenesis inhibitors[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2018,152:307-317.
APA	Ma, Fei.,Liu, Jian.,Zhou, Tingting.,Lei, Min.,Chen, Jing.,...&Hu, Lihong.(2018).Discovery and structure-activity relationships study of thieno[2,3-b] pyridine analogues as hepatic gluconeogenesis inhibitors.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,152,307-317.
MLA	Ma, Fei,et al."Discovery and structure-activity relationships study of thieno[2,3-b] pyridine analogues as hepatic gluconeogenesis inhibitors".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 152(2018):307-317.