MEDICINAL CHEMISTRY OF NOVEL ANTITHROMBOTIC DRUGS

血小板聚集调节的一个重要的新机制是 发现蛋白激酶C介导的激活 血小板颗粒的“释放”反应。 激活蛋白 激酶C导致一个40 KD蛋白的磷酸化，推测该蛋白是 释放各种血小板促聚集物质所必需的 从颗粒。 事实上，血小板可以被激活， 通过简单地加入某些甘油二酯。 这种新的激酶是 通过1，2-sn-甘油二酯的存在瞬时激活， 本身是多磷脂酰肌醇周转的产物。 该特定 通过1，2-Sn-甘油二酯的活化意味着该酶的特异性拮抗剂 酶是可以设计的。 申请资助的目的是 蛋白激酶C激活和抑制的药物化学。 新的甘油二酯类似物将被合成和结构-活性 这些分子作为蛋白激酶C激动剂和拮抗剂的研究 活动将进行。 激动剂的原型结构和 将确定拮抗剂。 这两种分子都将被检测 它们引起和干扰血小板聚集的活性， 体外 活性拮抗剂将作为合理设计的基础， 干扰血小板聚集的药物， 治疗血栓性和血栓栓塞性疾病的抗血栓药物 主要是动脉型的疾病。

An important new mechanism in the regulation platelet aggregation was uncovered with the discovery of the protein kinase-C mediated activation of the "release" reaction from platelet granules. The activation of protein kinase-C leads to the phosphorylation of a 40 KD protein presumed to be necessary for the release of various platelet proaggregatory substances from the granules. Indeed platelets can be activated towards aggregation by the simple addition of certain diglycerides. This new kinase is transiently activated by the presence of 1,2-sn-diglycerides, which are themselves products of polyphosphatidylinositol turnover. This specific activation by 1,2-sn-diglycerides means that specific antagonists of this enzyme can be designed. It is the purpose of this grant request to explore the medicinal chemistry of protein kinase-C activation and inhibition. Novel diglyceride analogs will be synthesized and structure-activity studies on these molecules as agonists and antagonists of protein kinase-C activity will be performed. The prototypical structures of agonists and antagonists will be determined. Both kinds of molecules will be tested for their activities to cause and interfere with platelet aggregation in vitro. Active antagonists will serve as a basis for the rational design of drugs which interfere with platelet aggregation to be utilized as antithrombotic drugs in the treatment of thrombotic and thromboembolic disease primarily of the arterial type.