Conjugates of Tetramethylpyrazine' metabolites and amino acid as potential antiplatelet agents
Conjugates of Tetramethylpyrazine' metabolites and amino acid as potential antiplatelet agents
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DOI：
10.1007/s00044-021-02817-3
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发表时间：
2021-11-12
影响因子：
2.6
通讯作者：
Dong, Li
中科院分区：
文献类型：
--
作者：
Dong, Yongxi;Wu, Shuxia;Dong, Li
川芎嗪是临床常用的抗血小板药物。但其半衰期短、生物利用度低限制了其应用。3，5，6-三甲基吡嗪-2-羧酸（TMP-COOH）和2-羟基-3，5，6-三甲基吡嗪（TMP-OH）是TMP在体内的两种主要活性代谢产物。两者均具有抗血小板聚集活性，但代谢快，具有明显的缺点。在本研究中，设计了TMP-COOH/TMP-OH与氨基酸的缀合物来解决这个问题。我们证明，20个缀合物中有13个显示出比TMP更高的抗血小板聚集活性。优化后的化合物4a具有降低凝血功能，延长出血时间、凝血酶时间、凝血酶原时间、活化部分凝血时间和降低纤维蛋白原含量的作用。综上所述，我们证明了缀合策略可以用于开发用于抗血小板剂的TMP衍生物。[图形]。
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.[GRAPHICS].