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Discovery of 5-methyl-2-(4-((4-(methylsulfonyl)benzyl)oxy)phenyl)-4-(piperazin-1-yl)pyrimidine derivatives as novel GRP119 agonists for the treatment of diabetes and obesity

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Abstract

A series of fused-pyrimidine derivatives were prepared and evaluated for their agonistic activities against human GPR119. Compound 9i showed high potent agonistic activity against HEK293T cells over-expressing human GPR119 and improved glucose tolerance in dose-dependent manner, as well as promoted insulin secretion. In a DIO mice model, 9i also ameliorated the obese-related symptoms by decreasing the body weights without markedly changing food intake, normalized some serum biomarkers, such as ALT, AST, ALP, GLU, CHOL, HDL, and LDL, and exerted therapeutic activity on fat deposition in liver tissue. We consider 9i to have utility as a GPR119 agonists for the treatment of type 2 diabetes mellitus and obese-related symptoms.

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Acknowledgements

We are grateful to the National Key Programs of China during the 12th Five-Year Plan Period (Grant 2012ZX09103101-033).

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Author notes

  1. Jinying Chen and Zitai Sang have been contributed equally to this work.

Authors and Affiliations

  1. Chengdu Grain Storage Research Institute of SinoGrain, Cereals and Oils Inspection Center, Chengdu, China

    Jinying Chen

  2. Division of Nephrology, Kidney Research Institute, West China Hospital, West China Medical School Sichuan University, Chengdu, 610041, China

    Zitai Sang, Linhong He & Liang Ma

  3. College of Life Sciences, Sichuan University, Chengdu, China

    Lu Li

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  1. Jinying Chen
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  2. Zitai Sang
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  3. Lu Li
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Corresponding author

Correspondence to Jinying Chen.

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Supporting information 1H NMR, 13C analysis of synthesized compounds. (doc 25,998KB).

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Chen, J., Sang, Z., Li, L. et al. Discovery of 5-methyl-2-(4-((4-(methylsulfonyl)benzyl)oxy)phenyl)-4-(piperazin-1-yl)pyrimidine derivatives as novel GRP119 agonists for the treatment of diabetes and obesity. Mol Divers 21, 637–654 (2017). https://doi.org/10.1007/s11030-017-9755-6

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