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，沿着拆分 凝血酶的晶体结构，现在有可能开创一种 新一代临床上有用的抗血栓剂。 长期 这项研究的目标是设计，合成和测试有效的新的 适用于临床的低分子量抗血栓形成剂， 在肝素和阿司匹林无效的情况下。 虽然 目前使用的抗血栓药物有几类， 防止通过溶栓清除的某些患病动脉再闭塞，或 与患者手术治疗相关的闭塞并发症 血管疾病 显然，需要更有效地 抗血栓药物 凝血酶和产生凝血酶的酶是丝氨酸 具有胰蛋白酶样特异性的蛋白酶。 凝血酶具有关键作用， 血小板在动脉血栓形成过程中的活化， 除了介导富含纤维蛋白的血栓形成之外。 小分子 重量凝血酶抑制剂将消除动脉血栓的形成， 一种对肝素有抵抗力的过程。 因此，基于机制和 凝血酶或产生凝血酶的酶的过渡态抑制剂 凝血酶可能是临床上有用的抗凝剂。 基于机理和过渡态的抑制剂具有以下优点： 强效，对靶酶特异，不与其他蛋白质反应， 因此无毒。 凝血酶X射线结构的最新解析 为解决凝血酶抑制剂的结构提供了机会 配合物和使用计算机辅助分子模拟设计新的 更有效的凝血酶抑制剂结构。 本研究中合成的抑制剂将进行测试， 1)使用纯化的凝血丝氨酸的体外效力和特异性 蛋白酶，2）在血浆中的稳定性，3）抑制蛋白酶复合物的能力， 凝血蛋白酶及其天然辅因子，以及4）在以下方面的功效： 小动物模型 在这项研究中产生的抑制剂将 对治疗和通过动力学分析、X射线 衍射分析、体外凝血试验和体内试验将 为血栓形成和止血提供了重要的新见解， 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.