MEDICINAL CHEMISTRY OF NOVEL ANTITHROMBOTIC DRUGS

调节血小板聚集的一个重要新机制是 发现蛋白激酶-C介导的激活 血小板颗粒的“释放”反应。蛋白质的活化 激酶C导致40kD蛋白的磷酸化，推测该蛋白是 释放各种血小板聚集物质所必需的 从颗粒中分离出来。事实上，血小板可以被激活以进行聚集 通过简单地添加某些二甘油酯。这种新的激活剂是 通过1，2-SN-二甘油酯的存在而瞬时激活，该二甘油酯是 自身产物聚磷脂酰肌醇周转。这个特定的 被1，2-SN-二甘油酯激活意味着该受体的特定拮抗剂 酶是可以设计的。这项拨款申请的目的是探索 蛋白激酶C激活和抑制的药物化学。 新型双甘油三酯类似物的合成及其构效关系 这些分子作为蛋白激酶C激动剂和拮抗剂的研究 将进行活动。激动剂和激动剂的原型结构 对抗者将是坚定的。这两种分子都将接受测试 它们引起和干扰血小板聚集的活性 体外培养。积极的拮抗剂将作为合理设计的基础 干扰血小板聚集的药物将用作 血栓形成和血栓栓塞症治疗中的抗血栓药物 主要为动脉型的疾病。

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.