Small molecule IVQ, as a prodrug of gluconeogenesis inhibitor QVO, efficiently ameliorates glucose homeostasis in type 2 diabetic mice
文献类型：期刊论文
| 作者 | Zhou, Ting-ting2; Zhao, Tong3; Ma, Fei4; Zhang, Yi-nan3; Jiang, Jing3; Ruan, Yuan3; Yan, Qiu-ying3; Wang, Gai-hong4; Ren, Jin4 ; Guan, Xiao-wei3
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| 刊名 | ACTA PHARMACOLOGICA SINICA
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| 出版日期 | 2019-09-01 |
| 卷号 | 40期号:9页码:1193-1204 |
| 关键词 | type 2 diabetes mellitus hepatic gluconeogenesis AMPK signaling pathway (E)-3-(2-(quinoline-4-yl)vinyl)-1H-indol-6-ol (QVO) 4-[2-(1H-indol-3-yl)vinyl]quinoline (IVQ) prodrug |
| ISSN号 | 1671-4083 |
| DOI | 10.1038/s41401-018-0208-2 |
| 通讯作者 | Hu, Li-hong(lhhu@njucm.edu.cn) ; Chen, Jing(jingchen@simm.ac.cn) ; Shen, Xu(xshen@njucm.edu.cn) |
| 英文摘要 | 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. |
| WOS关键词 | ACTIVATED PROTEIN-KINASE ; HEPATIC GLUCONEOGENESIS ; COMPLEX I ; THERAPEUTIC TARGET ; METABOLIC DISEASES ; AMPK ; METFORMIN ; PHOSPHORYLATION ; CYTOCHROME-P450 ; HYDROXYLATION |
| 资助项目 | National Natural Science Foundation of China[81473141] ; National Natural Science Foundation of China[81703806] ; National Natural Science Foundation of China[81800430] ; NSFC-TRF collaboration projects[NSFC 81561148011] ; Priority Academic Program Development of Jiangsu Higher Education Institutions (Integration of Chinese and Western Medicine) ; Fundamental Research Funds for the Central Universities[JUSRP11863] ; China Postdoctoral Science Foundation[2018M642172] |
| WOS研究方向 | Chemistry ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000484000100006 |
| 出版者 | NATURE PUBLISHING GROUP |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/288773]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Hu, Li-hong; Chen, Jing; Shen, Xu |
| 作者单位 | 1.Univ Macau, Inst Chinese Med Sci, Macau, Peoples R China 2.Jiangnan Univ, Wuxi Sch Med, Wuxi 214122, Jiangsu, Peoples R China 3.Nanjing Univ Chinese Med, Sch Med & Life Sci, State Key Lab Cultivat Base TCM Qual & Efficacy, Nanjing 210023, Jiangsu, Peoples R China 4.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China 5.RMIT Univ, Sch Hlth & Biomed Sci, POB 71, Melbourne, Vic 3083, Australia |
| 推荐引用方式 GB/T 7714 | Zhou, Ting-ting,Zhao, Tong,Ma, Fei,et al. Small molecule IVQ, as a prodrug of gluconeogenesis inhibitor QVO, efficiently ameliorates glucose homeostasis in type 2 diabetic mice[J]. ACTA PHARMACOLOGICA SINICA,2019,40(9):1193-1204. |
| APA | Zhou, Ting-ting.,Zhao, Tong.,Ma, Fei.,Zhang, Yi-nan.,Jiang, Jing.,...&Shen, Xu.(2019).Small molecule IVQ, as a prodrug of gluconeogenesis inhibitor QVO, efficiently ameliorates glucose homeostasis in type 2 diabetic mice.ACTA PHARMACOLOGICA SINICA,40(9),1193-1204. |
| MLA | Zhou, Ting-ting,et al."Small molecule IVQ, as a prodrug of gluconeogenesis inhibitor QVO, efficiently ameliorates glucose homeostasis in type 2 diabetic mice".ACTA PHARMACOLOGICA SINICA 40.9(2019):1193-1204. |
入库方式： OAI收割
来源：上海药物研究所
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