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MEDICINAL CHEMISTRY OF NOVEL ANTITHROMBOTIC DRUGS

新型抗血栓药物的药物化学

基本信息

批准号：
3347146
负责人：
ROBERT R RANDO
金额：
$ 16.48万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
1985
资助国家：
美国
起止时间：
1985-09-01 至 1989-08-31
项目状态：
已结题

项目摘要

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.

调节血小板聚集的一个重要新机制是发现了蛋白激酶-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 40 KD 蛋白质的磷酸化，推测是释放各种血小板促聚集物质所必需的来自颗粒。事实上，血小板可以被激活以聚集通过简单添加某些甘油二酯。这种新激酶是 1,2-sn-甘油二酯的存在会短暂激活，本身是多磷脂酰肌醇营业额的产品。这个具体 1,2-sn-二甘油酯的激活意味着该物质的特异性拮抗剂可以设计酶。本次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。新型甘油二酯类似物的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将进行活动。激动剂和激动剂的原型结构拮抗剂将被确定。两种分子都将进行测试它们引起和干扰血小板聚集的活动体外。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可用作抗血栓药物在血栓形成和血栓栓塞治疗中的应用主要是动脉类型的疾病。