SYNTHETIC ANTITHROMBOTIC AGENTS

基于机制(或自杀)的设计的最新进展 丝氨酸蛋白酶的过渡态抑制剂及其拆分 凝血酶的晶体结构，现在使人们有可能开创一种 新一代临床有用的抗血栓药物。从长远来看 这项研究的目标是设计、合成和测试有效的新 适合临床使用的低分子抗血栓药物 在肝素和阿司匹林无效的情况下。虽然 目前有几类抗血栓药物在使用，没有一种 防止部分病变动脉溶栓或清除后再闭塞 与手术治疗相关的闭塞并发症 患有血管疾病。显然，有必要更有效地 抗血栓药物。 凝血酶和产生凝血酶的酶是丝氨酸 具有类胰酶专一性的蛋白酶。凝血酶在以下方面起着关键作用 大鼠动脉血栓形成过程中血小板的活化 此外还能调节富含纤维蛋白的血栓的形成。小分子 重量级的凝血酶抑制剂将消除动脉血栓的形成， 对肝素有抵抗力的过程。因此，基于机制的和 凝血酶或其所产生的酶的过渡态抑制物 凝血酶可能是临床上有用的抗凝血剂。 基于机理的和过渡态抑制剂的优点是 有效的，特定于目标酶，不与其他蛋白质反应， 因此是无毒的。凝血酶X射线结构的最新解析 为解决凝血酶抑制物的结构提供了机会 并将计算机辅助分子模拟应用于新化合物的设计中 更有效的凝血酶抑制结构。 在这项研究中合成的抑制剂将被测试 1)纯化的凝血丝氨酸的体外效力和特异性 蛋白水解酶，2)在血浆中的稳定性，3)抑制复合物的能力 凝血酶及其天然辅助因子，以及4)在 小动物模型。在这项研究中产生的抑制剂将是 可能对治疗和他们的研究有用的动力学分析，x射线 将进行衍射分析、体外凝血试验和体内试验 为血栓形成和止血提供重要的新见解 机制。

Recent advances in the design of mechanism-based (or suicide) and transition state inhibitors for serine proteases, along with the resolution of the crystal structure of thrombin, now makes it possible to pioneer a new generation of clinically useful antithrombotic agents. The long term goal of this research is the design, synthesis, and testing of potent new low molecular weight antithrombotic agents suitable for clinical use in humans in situations where heparin and aspirin are ineffective. Although there are several classes of antithrombotic drugs currently in use, none prevent reocclusion of some diseased arteries cleared by thrombolysis or the occlusive complications associated with surgical management of patients with vascular diseases. Clearly there is a need for more effective antithrombotic drugs. Thrombin and the enzymes which produce thrombin are serine proteases with trypsin-like specificity. Thrombin has a critical role in the activation of platelets during the formation of arterial thrombus in addition to mediating fibrin-rich thrombus formation. Small molecular weight thrombin inhibitors will abolish the formation of arterial thrombi, a process that is resistant to heparin. Thus, mechanism-based and transition-state inhibitors for thrombin or the enzymes which generate thrombin are likely to be clinically useful anticoagulants. Mechanism-based and transition state inhibitors have the advantage of being potent, specific for the target enzyme, unreactive with other proteins and thus non-toxic. The recent resolution of the x-ray structure of thrombin presents the opportunity for solving the structures of thrombin-inhibitor complexes and using computer-aided molecular modeling in the design of new more potent inhibitor structures for thrombin. The inhibitors synthesized in this research will be tested for 1) in vitro potency and specificity using purified coagulation serine proteases, 2) stability in plasma, 3) ability to inhibit complexes of coagulation proteases with their natural cofactors, and 4) efficacy in small animal models. The inhibitors produced in this research will be potentially useful for therapy and their study by kinetic analysis, x-ray diffraction analysis, in vitro coagulation tests, and in vivo testing will provide important new insights into thrombogenesis and the hemostatic mechanism.