抗凝血药物是抗血栓治疗的主要手段，口服直接FXa抑制剂作为目前最具有开发前景的抗血栓药物，不仅具有高效的抗凝血活性，同时避免了传统抗血栓药物的一些弊端，使其有可能成为疗效和安全性俱佳的新一代抗血栓药物。本项目将在已有工作的基础上，以利伐沙班为先导药物，并结合本领域结构生物学最新成果，设计、合成100个结构通式如图7所示的全新母核结构的高活性的直接FXa抑制剂，深入研究其构效、构代、构毒关系，探索这类新三环结构和生物效应之间的规律，以及这类多手性、复杂分子的立体选择性合成方法，为设计新一代FXa抑制剂积累知识基础。预计将申请专利2项，发表高水平研究论文2-4篇，争取发现1-2个抗血栓活性强，代谢性质优良，毒性低的具有开发前景的候选药物，为最终开发出拥有我国自主知识产权的创新药物奠定坚实的知识基础。

Thromboembolic diseases are leading causes of cardiovascular-associated morbidity and death.A direct inhibitor of FXa is an attactive therapeutic target for prevention and treatment of thrombotic diseases.In contrast to the multifunctional role that thrombin plays in the blood coagulation cascade, FXa only converts prothrombin to thrombin but does not affect the existing level of circulating thrombin. So it has been proposed that FXa inhibitor may exhibit a reduced bleeding risk and offer a superior safety/efficacy profile with respect to thrombin inhibitor.In an attempt to find novel potent and safety FXa inhibitors, the project will be focus on discovering new FXa inhibitors with novel tricycli structure based our previous work.In this proposed project, 100 new inhibitors will be prepared and their structure -activity/toxicity/metabolism ralationship were evaluated. Meanwhile the synthesis methods for the inhibitors with multiple chiral center were be established. This project will lay a solid foundation to provide promising candidates as a new generation of direct FXa inhibitor in the future.