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Small molecule IVQ, as a prodrug of gluconeogenesis inhibitor QVO, efficiently ameliorates glucose homeostasis in type 2 diabetic mice

Abstract

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 β- 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.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (Grant numbers 81473141, 81703806, 81800430), NSFC-TRF collaboration projects (Grant numbers NSFC 81561148011), the Priority Academic Program Development of Jiangsu Higher Education Institutions (Integration of Chinese and Western Medicine), the Fundamental Research Funds for the Central Universities (Grant number JUSRP11863), and Project funded by China Postdoctoral Science Foundation (Grant number 2018M642172).

Author contributions

XS, JC, and TTZ were responsible for the conception and design of the study. TTZ, TZ, YR, QYY, and GHW designed and performed experiments. FM, YNZ, JJ, and LHH contributed to the acquisition of IVQ-HCl. TTZ and XS were responsible for drafting the manuscript. JR, XWG, JG, YHZ, and JMY gave advice on the manuscript preparation. XS is the guarantor of this work and, as such, has full access to all the data in the study and takes responsibility for the integrity of the data and accuracy of the data analysis. All authors approved the manuscript.

Author information

Correspondence to Li-hong Hu or Jing Chen or Xu Shen.

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The authors declare no competing interests.

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Keywords

  • 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
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