PMID- 29733999 OWN - NLM STAT- MEDLINE DCOM- 20180619 LR - 20180620 IS - 1768-3254 (Electronic) IS - 0223-5234 (Linking) VI - 152 DP - 2018 May 25 TI - Discovery and structure-activity relationships study of thieno[2,3-b]pyridine analogues as hepatic gluconeogenesis inhibitors. PG - 307-317 LID - S0223-5234(18)30362-3 [pii] LID - 10.1016/j.ejmech.2018.04.028 [doi] AB - 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: IC(50) = 33.8 muM) 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 CF(3) in the thienopyridine core could improve the potency and led to the discovery of 8e (IC(50) = 16.8 muM) and 9d (IC(50) = 12.3 muM) 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. CI - Copyright (c) 2018 Elsevier Masson SAS. All rights reserved. FAU - Ma, Fei AU - Ma F AD - Jiangsu Key Laboratory for Functional Substance of Chinese Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Stake Key Laboratory Cultivation Base for TCM Quality and Efficacy, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; Department of Chemistry, Kansas State University, Manhattan, KS, 66506, United States. FAU - Liu, Jian AU - Liu J AD - Jiangsu Key Laboratory for Functional Substance of Chinese Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Stake Key Laboratory Cultivation Base for TCM Quality and Efficacy, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China. FAU - Zhou, Tingting AU - Zhou T AD - State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; School of Medicine, Jiangnan University, Wuxi, 214122, China. FAU - Lei, Min AU - Lei M AD - State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China. FAU - Chen, Jing AU - Chen J AD - State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China. FAU - Wang, Xiachang AU - Wang X AD - Jiangsu Key Laboratory for Functional Substance of Chinese Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Stake Key Laboratory Cultivation Base for TCM Quality and Efficacy, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China. FAU - Zhang, Yinan AU - Zhang Y AD - Jiangsu Key Laboratory for Functional Substance of Chinese Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Stake Key Laboratory Cultivation Base for TCM Quality and Efficacy, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China. FAU - Shen, Xu AU - Shen X AD - Jiangsu Key Laboratory for Functional Substance of Chinese Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Stake Key Laboratory Cultivation Base for TCM Quality and Efficacy, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China. Electronic address: xshen@simm.ac.cn. FAU - Hu, Lihong AU - Hu L AD - Jiangsu Key Laboratory for Functional Substance of Chinese Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Stake Key Laboratory Cultivation Base for TCM Quality and Efficacy, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China. Electronic address: lhhu@njucm.edu.cn. LA - eng PT - Journal Article DEP - 20180424 PL - France TA - Eur J Med Chem JT - European journal of medicinal chemistry JID - 0420510 RN - 0 (Hypoglycemic Agents) RN - 0 (Pyridines) RN - 0 (thieno(2,3-b)pyridine) RN - IY9XDZ35W2 (Glucose) SB - IM MH - Animals MH - Dose-Response Relationship, Drug MH - *Drug Discovery MH - Gluconeogenesis/*drug effects/genetics MH - Glucose/*antagonists & inhibitors/biosynthesis MH - Glucose Tolerance Test MH - Hypoglycemic Agents/chemical synthesis/chemistry/*pharmacology MH - Liver/*drug effects/metabolism MH - Mice MH - Mice, Obese MH - Molecular Structure MH - Pyridines/chemical synthesis/chemistry/*pharmacology MH - Structure-Activity Relationship OTO - NOTNLM OT - Hepatic gluconeogenesis OT - Structure-activity relationships (SARs) OT - Thieno[2,3-b]pyridine derivatives OT - Type 2 diabetes mellitus (T2DM) EDAT- 2018/05/08 06:00 MHDA- 2018/06/21 06:00 CRDT- 2018/05/08 06:00 PHST- 2018/02/08 00:00 [received] PHST- 2018/03/31 00:00 [revised] PHST- 2018/04/14 00:00 [accepted] PHST- 2018/05/08 06:00 [pubmed] PHST- 2018/06/21 06:00 [medline] PHST- 2018/05/08 06:00 [entrez] AID - S0223-5234(18)30362-3 [pii] AID - 10.1016/j.ejmech.2018.04.028 [doi] PST - ppublish SO - Eur J Med Chem. 2018 May 25;152:307-317. doi: 10.1016/j.ejmech.2018.04.028. Epub 2018 Apr 24.