MEDICINAL CHEMISTRY OF NOVEL ANTITHROMBOTIC DRUGS

新型抗血栓药物的药物化学

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/3347146
• 关键词: anticoagulants; calcium; chelating agents; chemical structure function; croton oil; drug design /synthesis /production; ethylene glycols; fatty acid analog; hormone regulation /control mechanism; hydroxyl group; lipoprotein lipase; neurotransmitters; pentosyltransferase; phosphatidylcholines; phosphatidylinositols; phosphatidylserines; platelet aggregation; protein kinase C; stereochemistry

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.

一个重要的调控血小板聚集的新机制是