Chiu A T, Mousa S A, Pease L J, Roscoe W A, Bozarth J M, Reilly T M, Smith R D, Timmermans P B
Cardiovascular Diseases Research, Du Pont Merck Pharmaceutical Company, Wilmington, DE 19880-0400.
Biochem Biophys Res Commun. 1991 Sep 30;179(3):1500-8. doi: 10.1016/0006-291x(91)91742-u.
The efficacy and specificity of a novel synthetic thrombin inhibitor, DuP 714, on thrombin-induced elevation of cytoplasmic calcium, fibrinogen binding and aggregation in human platelets were examined. Thrombin (0.5 U/ml) stimulated an increase in [125I]fibrinogen binding in gel-filtered platelets which was blocked by DuP 714 with an IC50 value of 2 nM. Thrombin (1 U/ml)-induced elevation of intracellular [Ca2+]i was also blocked by DuP 714 with an IC50 value of 67 nM. A much higher concentration of thrombin (25 U/ml) was used to stimulate aggregation with heparinized platelet-rich plasma. Under these conditions, micromolar concentrations of DuP 714 were needed to inhibit thrombin. In all of these preparations, DuP 714 at concentrations as high as 10(-5) M had no intrinsic effects and did not affect the responses induced by arachidonate, ADP, collagen, epinephrine, vasopressin and serotonin. These data indicate that DuP 714 is a potent and specific thrombin inhibitor capable of arresting the actions of thrombin on human fibrin formation and platelet aggregation and secretion. It may serve as a potential antithrombotic agent for various forms of thrombotic disorders.
研究了一种新型合成凝血酶抑制剂DuP 714对凝血酶诱导的人血小板胞质钙升高、纤维蛋白原结合及聚集的疗效和特异性。凝血酶（0.5 U/ml）刺激凝胶过滤血小板中[125I]纤维蛋白原结合增加，DuP 714可阻断此作用，IC50值为2 nM。凝血酶（1 U/ml）诱导的细胞内[Ca2+]i升高也被DuP 714阻断，IC50值为67 nM。使用更高浓度的凝血酶（25 U/ml）刺激富含血小板的肝素化血浆聚集。在这些条件下，需要微摩尔浓度的DuP 714来抑制凝血酶。在所有这些制剂中，浓度高达10(-5) M的DuP 714无内在作用，且不影响花生四烯酸、ADP、胶原、肾上腺素、血管加压素和5-羟色胺诱导的反应。这些数据表明，DuP 714是一种强效且特异性的凝血酶抑制剂，能够阻止凝血酶对人纤维蛋白形成以及血小板聚集和分泌的作用。它可能作为一种潜在的抗血栓药物用于各种形式的血栓性疾病。
