PMID- 30833709 OWN - NLM STAT- MEDLINE DCOM- 20200205 LR - 20210422 IS - 1745-7254 (Electronic) IS - 1671-4083 (Print) IS - 1671-4083 (Linking) VI - 40 IP - 9 DP - 2019 Sep TI - Small molecule IVQ, as a prodrug of gluconeogenesis inhibitor QVO, efficiently ameliorates glucose homeostasis in type 2 diabetic mice. PG - 1193-1204 LID - 10.1038/s41401-018-0208-2 [doi] AB - Gluconeogenesis is a major source of hyperglycemia in patients with type 2 diabetes mellitus (T2DM), thus targeting gluconeogenesis to suppress glucose production is a promising strategy for anti-T2DM drug discovery. In our preliminary in vitro studies, we found that a small-molecule (E)-3-(2-(quinoline-4-yl)vinyl)-1H-indol-6-ol (QVO) inhibited the hepatic glucose production (HGP) in primary hepatocytes. We further revealed that QVO suppressed hepatic gluconeogenesis involving calmodulin-dependent protein kinase kinase beta- and liver kinase B1-adenosine monophosphate-activated protein kinase (AMPK) pathways as well as AMPK-independent mitochondrial function-related signaling pathway. To evaluate QVO's anti-T2DM activity in vivo, which was impeded by the complicated synthesis route of QVO with a low yield, we designed and synthesized 4-[2-(1H-indol-3-yl)vinyl]quinoline (IVQ) as a prodrug with easier synthesis route and higher yield. IVQ did not inhibit the HGP in primary hepatocytes in vitro. Pharmacokinetic studies demonstrated that IVQ was quickly converted to QVO in mice and rats following administration. In both db/db and ob/ob mice, oral administration of IVQ hydrochloride (IVQ-HCl) (23 and 46 mg/kg every day, for 5 weeks) ameliorated hyperglycemia, and suppressed hepatic gluconeogenesis and activated AMPK signaling pathway in the liver tissues. Furthermore, IVQ caused neither cardiovascular system dysfunction nor genotoxicity. The good druggability of IVQ has highlighted its potential in the treatment of T2DM and the prodrug design for anti-T2DM drug development. FAU - Zhou, Ting-Ting AU - Zhou TT AD - Wuxi School of Medicine, Jiangnan University, Wuxi, 214122, China. FAU - Zhao, Tong AU - Zhao T AD - State Key Laboratory Cultivation Base for TCM Quality and Efficacy, School of Medicine and Life Sciences, Nanjing University of Chinese Medicine, Nanjing, 210023, China. FAU - Ma, Fei AU - Ma F AD - Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. FAU - Zhang, Yi-Nan AU - Zhang YN AD - State Key Laboratory Cultivation Base for TCM Quality and Efficacy, School of Medicine and Life Sciences, Nanjing University of Chinese Medicine, Nanjing, 210023, China. FAU - Jiang, Jing AU - Jiang J AD - State Key Laboratory Cultivation Base for TCM Quality and Efficacy, School of Medicine and Life Sciences, Nanjing University of Chinese Medicine, Nanjing, 210023, China. FAU - Ruan, Yuan AU - Ruan Y AD - State Key Laboratory Cultivation Base for TCM Quality and Efficacy, School of Medicine and Life Sciences, Nanjing University of Chinese Medicine, Nanjing, 210023, China. FAU - Yan, Qiu-Ying AU - Yan QY AD - State Key Laboratory Cultivation Base for TCM Quality and Efficacy, School of Medicine and Life Sciences, Nanjing University of Chinese Medicine, Nanjing, 210023, China. FAU - Wang, Gai-Hong AU - Wang GH AD - Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. FAU - Ren, Jin AU - Ren J AD - Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. FAU - Guan, Xiao-Wei AU - Guan XW AD - State Key Laboratory Cultivation Base for TCM Quality and Efficacy, School of Medicine and Life Sciences, Nanjing University of Chinese Medicine, Nanjing, 210023, China. FAU - Guo, Jun AU - Guo J AD - State Key Laboratory Cultivation Base for TCM Quality and Efficacy, School of Medicine and Life Sciences, Nanjing University of Chinese Medicine, Nanjing, 210023, China. FAU - Zhao, Yong-Hua AU - Zhao YH AD - Institute of Chinese Medical Sciences, University of Macau, Macau, China. FAU - Ye, Ji-Ming AU - Ye JM AD - School of Health and Biomedical Sciences, RMIT University, PO Box 71, Melbourne, VIC, 3083, Australia. FAU - Hu, Li-Hong AU - Hu LH AD - State Key Laboratory Cultivation Base for TCM Quality and Efficacy, School of Medicine and Life Sciences, Nanjing University of Chinese Medicine, Nanjing, 210023, China. lhhu@njucm.edu.cn. FAU - Chen, Jing AU - Chen J AD - Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. jingchen@simm.ac.cn. FAU - Shen, Xu AU - Shen X AD - State Key Laboratory Cultivation Base for TCM Quality and Efficacy, School of Medicine and Life Sciences, Nanjing University of Chinese Medicine, Nanjing, 210023, China. xshen@njucm.edu.cn. LA - eng PT - Journal Article DEP - 20190304 PL - United States TA - Acta Pharmacol Sin JT - Acta pharmacologica Sinica JID - 100956087 RN - 0 (Enzyme Activators) RN - 0 (Enzyme Inhibitors) RN - 0 (Hypoglycemic Agents) RN - 0 (Indoles) RN - 0 (Prodrugs) RN - 0 (Quinolines) RN - EC 2.7.11.31 (AMP-Activated Protein Kinases) RN - EC 3.1.3.9 (Glucose-6-Phosphatase) RN - EC 4.1.1.32 (Phosphoenolpyruvate Carboxykinase (GTP)) RN - EC 7.1.1.2 (Electron Transport Complex I) RN - EC 7.1.1.8 (Electron Transport Complex III) SB - IM MH - AMP-Activated Protein Kinases/metabolism MH - Animals MH - Diabetes Mellitus, Experimental/drug therapy MH - Diabetes Mellitus, Type 2/*drug therapy MH - Electron Transport Complex I/antagonists & inhibitors MH - Electron Transport Complex III/antagonists & inhibitors MH - Enzyme Activators/therapeutic use/toxicity MH - Enzyme Inhibitors/therapeutic use/toxicity MH - Gluconeogenesis/*drug effects MH - Glucose-6-Phosphatase/antagonists & inhibitors MH - Hepatocytes/drug effects MH - Hypoglycemic Agents/*therapeutic use/toxicity MH - Indoles/*therapeutic use/toxicity MH - Liver/drug effects MH - Male MH - Mice, Inbred C57BL MH - Mitochondria/drug effects MH - Phosphoenolpyruvate Carboxykinase (GTP)/antagonists & inhibitors MH - Prodrugs/*therapeutic use/toxicity MH - Quinolines/*therapeutic use/toxicity MH - Signal Transduction/drug effects PMC - PMC6786289 OTO - NOTNLM OT - (E)-3-(2-(quinoline-4-yl)vinyl)-1H-indol-6-ol (QVO) OT - 4-[2-(1H-indol-3-yl)vinyl]quinoline (IVQ) OT - AMPK signaling pathway OT - hepatic gluconeogenesis OT - prodrug OT - type 2 diabetes mellitus COIS- The authors declare no competing interests. EDAT- 2019/03/06 06:00 MHDA- 2020/02/06 06:00 PMCR- 2020/09/01 CRDT- 2019/03/06 06:00 PHST- 2018/05/23 00:00 [received] PHST- 2018/12/23 00:00 [accepted] PHST- 2019/03/06 06:00 [pubmed] PHST- 2020/02/06 06:00 [medline] PHST- 2019/03/06 06:00 [entrez] PHST- 2020/09/01 00:00 [pmc-release] AID - 10.1038/s41401-018-0208-2 [pii] AID - 208 [pii] AID - 10.1038/s41401-018-0208-2 [doi] PST - ppublish SO - Acta Pharmacol Sin. 2019 Sep;40(9):1193-1204. doi: 10.1038/s41401-018-0208-2. Epub 2019 Mar 4.