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Conjugates of Tetramethylpyrazine’ metabolites and amino acid as potential antiplatelet agents

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Abstract

Tetramethylpyrazine (TMP) is commonly used as an antiplatelet drug in clinic. However, the short half-life and low bioavailability limited its applications. 3, 5, 6-Trimethylpyrazine-2-carboxAylic acid (TMP-COOH) and 2-hydroxy-3, 5, 6-trimethylpyrazine (TMP-OH) are the two major active metabolites of TMP in vivo. Both displayed antiplatelet aggregation activity but have obvious disadvantage of rapid metabolism. In this study, conjugates of TMP-COOH/TMP-OH with amino acids were designed to address this issue. We demonstrated that 13 out of 20 conjugates displayed higher antiplatelet aggregation activity than TMP. The optimized compound 4a was further proved to reduce clot retraction, prolong the bleeding time, thrombin time, prothrombin time, activated partial thromboplatin time and reduce fibrinogen content. Taken together, we demonstrated the conjugation strategy could be exploited to develop TMP derivatives for antiplatelet agents.

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Acknowledgements

This work was supported by National Natural Science Foundation of China (Nos. U1812403 and 81960630), the Department of Science and Technology of Guizhou Province (Nos. 2020-5006, 2020-6011 and 2018-5779), the Department of Education of Guizhou Province (No. 2021-164).

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Author notes

  1. These authors contributed equally: Yongxi Dong, Shuxia Wu

Authors and Affiliations

  1. State Key Laboratory of Functions and Applications of Medicinal Plants & School of Pharmacy, Guizhou Medical University, Guian New District, Guiyang, 550025, Guizhou, China

    Yongxi Dong, Shuxia Wu, Mingji Liu, Jiayu Huang, Yuanhu Mao, Jiquan Zhang, Zhanzhan Yang, Shanggao Liao & Li Dong

  2. Guizhou provincial Center for Disease Control and Prevention, Guiyang, 550004, Guizhou, China

    Lei Li

  3. Guizhou Provincial Key Laboratory of Pathogenesis & Drug Research on Common Chronic Diseases & School of Basic Medical Sciences, Guizhou Medical University, Guian New District, Guiyang, 550025, Guizhou, China

    Gang Liu

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  1. Yongxi Dong
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Correspondence to Gang Liu, Shanggao Liao or Li Dong.

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Dong, Y., Wu, S., Liu, M. et al. Conjugates of Tetramethylpyrazine’ metabolites and amino acid as potential antiplatelet agents. Med Chem Res 31, 75–84 (2022). https://doi.org/10.1007/s00044-021-02817-3

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  • DOI: https://doi.org/10.1007/s00044-021-02817-3

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