PDF(Pubmed)
Abstract：
A new family of antifibrinolytic drugs has been recently discovered, combining a triazole moiety, an oxadiazolone, and a terminal amine. Two of the molecules of this family have shown activity that is greater than or similar to that of tranexamic acid (TXA), the current antifibrinolytic gold standard, which has been associated with several side effects and whose use is limited in patients with renal impairment. The aim of this work was to thoroughly examine the mechanism of action of the two ideal candidates of the 1,2,3-triazole family and compare them with TXA, to identify an antifibrinolytic alternative active at lower dosages. Specifically, the antifibrinolytic activity of the two compounds (1 and 5) and TXA was assessed in fibrinolytic isolated systems and in whole blood. Results revealed that despite having an activity pathway comparable to that of TXA, both compounds showed greater activity in blood. These differences could be attributed to a more stable ligand-target binding to the pocket of plasminogen for compounds 1 and 5, as suggested by molecular dynamic simulations. This work presents further evidence of the antifibrinolytic activity of the two best candidates of the 1,2,3-triazole family and paves the way for incorporating these molecules as new antifibrinolytic therapies.
摘要：
最近发现了一个新的抗纤维蛋白溶解药物家族，结合三唑部分，恶二唑酮,和末端胺。该家族的两个分子显示出大于或类似于氨甲环酸（TXA）的活性，目前的抗纤维蛋白溶解金标准，它与几种副作用有关，并且在肾损害患者中的使用有限。这项工作的目的是彻底检查1,2,3-三唑家族的两个理想候选者的作用机制，并将它们与TXA进行比较，以确定在较低剂量下具有活性的抗纤维蛋白溶解替代品。具体来说,在纤溶分离系统和全血中评估了两种化合物（1和5）和TXA的抗纤溶活性。结果表明，尽管具有与TXA相当的活性途径，两种化合物在血液中显示出更大的活性。这些差异可归因于化合物1和5与纤溶酶原口袋的更稳定的配体-靶标结合,如分子动力学模拟所提示的。这项工作提供了1,2,3-三唑家族的两个最佳候选者的抗纤维蛋白溶解活性的进一步证据，并为将这些分子作为新的抗纤维蛋白溶解疗法铺平了道路。
