SYNTHESIS AND TESTING OF A NEW CLASS OF HEPARINOIDS

这个项目的总体目标是开发一种替代物 对于可以口服的肝素。肝素目前 预防和初期治疗的首选药物 血栓栓塞性疾病。它会立即产生一种抗凝剂 在血浆中存在时的作用，并可静脉给药 或皮下注射(但不是口服)。出血和血小板减少症 是与肝素治疗有关的毒性。这项建议 解决急性抗凝缺乏替代药物的问题。 在第一阶段克期间，我们合成了硫酸盐 具有体外抗凝血剂和抗凝血剂的双二糖酸酰胺 抗血栓活性。最活跃的化合物， 由麦芽仿生酸与一种独特的连接物合成 口服后几分钟内的体内抗凝活性 在兔体内给药，持续时间超过8小时。我们有 获得了这种化合物的专利。我们建议继续 麦芽仿酸衍生物的体内检测及鉴定 并对其作用机制和药效学进行研究。这个 这种化合物用于临床的优点包括易于 给药，起效快，化学成分均一， 可以减少或消除与以下相关的毒性 肝素疗法。 建议的商业应用：提供备选方案的能力 替代肝素治疗血栓栓塞症的药物 疾病具有重大的医学和商业意义。

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.