SYNTHESIS AND TESTING OF A NEW CLASS OF HEPARINOIDS

新型类肝素的合成和测试

• 批准号: 6349584
• 负责人: JOSEPH A TOCE
• 金额: $ 10.99万
• 依托单位: RELIABLE BIOPHARMACEUTICAL CORPORATION
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-09-30 至 2001-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6349584
• 关键词: anticoagulants; chemical synthesis; drug design /synthesis /production; heparin; high performance liquid chromatography; laboratory rabbit; laboratory rat; lactones; nonhuman therapy evaluation; oral administration; pharmacokinetics; thrombocytopenia; thromboembolism

The overall objective of this project is to develop a replacement for heparin that can be orally administered. Heparin is currently the drug of choice for the prophylaxis and initial therapy of thromboembolic disease. It produces an immediate anticoagulant effect when present in plasma and can be administered intravenously or subcutaneously (but not orally). Bleeding and thrombocytopenia are toxicities associated with heparin therapy. This proposal addresses the lack of alternative drugs for acute anticoagulation. During the Phase I gram period we synthesized sulfated bis-disaccharide acid amides that have in vitro anticoagulant and antithrombotic activities. The most active compound, synthesized from maltobionic acid with a unique linker demonstrated in vivo anticoagulant activity within IS minutes of oral administration in rabbits and lasted for over eight hours. We have been awarded a patent for this compound. We propose to continue the testing of this maltobionic acid derivative in vivo and to identify its mechanism of action and study its pharmacodynamics. The advantages of this compound for clinical use would include ease of administration , rapid onset of action and chemical homogeneity, which could reduce or eliminate the toxicities associated with heparin therapy. PROPOSED COMMERCIAL APPLICATIONS: The ability to offer alternate drugs to replace Heparin in treating thromboembolic disease is of major medical and commercial significance.

该项目的总体目标是开发一种替代 用于口服的肝素。肝素目前 预防和初始治疗的首选药物 血栓栓塞性疾病它能产生一种即时的抗凝血剂 当存在于血浆中并可静脉内给药时有效 或皮下注射（但不是口服）。出血和血小板减少 是与肝素治疗相关的毒性。这项建议 解决了急性抗凝治疗缺乏替代药物的问题。 在第一阶段，我们合成了硫酸盐 具有体外抗凝剂的双二糖酰胺， 抗血栓活性。最活跃的化合物， 由麦芽糖酸合成，具有独特的连接体， 口服15分钟内的体内抗凝活性 给药，持续8小时以上。我们有 获得了这种化合物的专利。我们建议继续 在体内测试该麦芽糖酸衍生物并鉴定 研究其作用机制和药效学。的 该化合物用于临床的优点包括易于 给药、快速起效和化学均匀性， 这可以减少或消除与 肝素治疗 拟议的商业应用：提供替代 治疗血栓栓塞性疾病的肝素替代药物 疾病具有重大的医学和商业意义。