Reilly T M, Knabb R M, Hassell S M, Bozarth J M, Forsythe M S, Mayo M C, Racanelli A L, Mousa S A
Du Pont Merck Pharmaceutical Company, Wilmington, DE 19880-0400.
Blood Coagul Fibrinolysis. 1992 Oct;3(5):513-7. doi: 10.1097/00001721-199210000-00001.
Since thrombin plays an important role in platelet-mediated arterial thrombosis, we have examined the antiplatelet activity of a synthetic thrombin inhibitor, DuP 714 (Ac-(D)Phe-Pro-boroArg), in comparison with that of the naturally occurring inhibitor hirudin. Hirudin was slightly more potent than DuP 714 in inhibiting thrombin-induced aggregation in washed human platelets (IC50s of 72 nM and 150 nM, respectively) and in inhibiting the secretion of plasminogen activator inhibitor-I from human platelets (IC50s of 300 nM and 900 nM, respectively). In contrast, DuP 714 was more potent than hirudin in inhibiting thrombin-induced [125I]fibrinogen binding to gel purified platelets, and in inhibiting thrombin-induced intracellular calcium mobilization in washed platelets. These results indicate that the tripeptide DuP 714 has comparable antiplatelet activity to the 65 amino acid hirudin. We conclude that DuP 714 may have clinical utility in the prevention of platelet-dependent, arterial thrombotic processes.
由于凝血酶在血小板介导的动脉血栓形成中起重要作用，我们研究了一种合成凝血酶抑制剂DuP 714（Ac-(D)Phe-Pro-boroArg）的抗血小板活性，并与天然存在的抑制剂水蛭素进行了比较。在抑制凝血酶诱导的洗涤人血小板聚集方面（IC50分别为72 nM和150 nM）以及在抑制人血小板中纤溶酶原激活物抑制剂-I的分泌方面（IC50分别为300 nM和900 nM），水蛭素比DuP 714稍强。相比之下，在抑制凝血酶诱导的[125I]纤维蛋白原与凝胶纯化血小板的结合以及在抑制凝血酶诱导的洗涤血小板细胞内钙动员方面，DuP 714比水蛭素更强。这些结果表明三肽DuP 714具有与65个氨基酸的水蛭素相当的抗血小板活性。我们得出结论，DuP 714在预防血小板依赖性动脉血栓形成过程中可能具有临床应用价值。
