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

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 o...

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Bibliographic Details
Published in:Medicinal chemistry research 2022, Vol.31 (1), p.75-84
Main Authors: Dong, Yongxi, Wu, Shuxia, Liu, Mingji, Huang, Jiayu, Mao, Yuanhu, Zhang, Jiquan, Yang, Zhanzhan, Li, Lei, Liu, Gang, Liao, Shanggao, Dong, Li
Format: Article
Language:English
Subjects:
Agglomeration
Amino acids
Antiplatelet therapy
Bioavailability
Biochemistry
Biomedical and Life Sciences
Biomedicine
Bioorganic Chemistry
Conjugates
Conjugation
Fibrinogen
Inorganic Chemistry
Medicinal Chemistry
Metabolites
Original Research
Pharmacology/Toxicology
Prothrombin
Thrombin
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Summary: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.
ISSN:1054-2523
1554-8120
DOI:10.1007/s00044-021-02817-3