血栓性疾病的药物治疗尚不理想，是未满足的治疗需求。凝血酶受体-1（PAR1）是较理想的抗血小板药物作用靶点，具有高安全性和高效性等特点。利用天然产物手性骨架能够简便高效的构建结构复杂的手性药物分子，简化制备工艺、节约成本。基于天然产物穿心莲内酯中的手性骨架与靶向PAR1的唯一上市药物Vorapaxar中复杂的手性骨架基本一致的特点，本课题拟借助穿心莲内酯的手性骨架，替代Vorapaxar相对应部分，快速、高效地制备系列结构新颖的PAR1拮抗剂。同时，在我们的前期研究基础上利用分子模拟及三维定量构效关系（3D-QSAR）分析，进一步指导化合物的结构优化，合理设计、合成系列PAR1拮抗剂。以抑制PAR1靶点、体内外抗血小板活性评价及药代动力学指标为指导，设计合成与发现结构新颖的PAR1拮抗剂先导化合物或候选药物，为新型抗凝血酶抑制剂的研发提供药物化学的基础。

The drug treatment of thrombotic diseases is not ideal and it’s an unmet clinical needs. Thus, novel antiplatelet drugs need to be developed. Protease-activated receptor-1 (PAR1) is regarded as a promising antithrombosis target that is less likely to result in bleeding. The scaffolds of natural products could be used in the construction and preparation of complex molecules in a more convenient and efficient way. Since the chiral fragment of bicyclic ring of andrographolide is consistent with that of an FDA approved drug Vorapaxar – the only antiplatelet drug targeting PAR1, this study intends to use the chiral skeleton of andrographolide to replace the corresponding fragment of Vorapaxar to facilitate the efficient and rapid construction of Vorapaxar analogues. Furthermore, molecular modeling and three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis are used to guide the structural optimization of PAR1 antagonists. Finally, the novel PAR1 antagonist drug candidates will be used to study their antithrombotic activity, antiplatelet aggregation in vivo and in vitro, and their pharmacokinetic properties.