血栓可致心梗和脑梗等严重后果。患者体内的血栓是血小板活化诱发的两种机理形成的血栓混合体。一种是血小板膜内α-颗粒外吐P-选择素造成的血栓，一种是糖蛋白IIb/IIIa外化和变构造成的血栓。已知的药物设计通常只针对其中一种血栓。基于血栓对两种机理的依赖性和分子建模技术,申请人设计四氢异喹啉-3-甲酰基-TARGD(F)F同时阻断了两种机理及血栓形成。借助计算机模拟预测，它的T换为L或P，F换为S或V组成的8种新化合物更优秀。本项目拟合成这8种新化合物、研究这8种新化合物对P-选择素和糖蛋白IIb/IIIa的抑制活性、评价这8种新化合物的抗血小板聚集和抗血栓活性、研究这8种新化合物的作用机理。在科学层面，该研究会带来创新并揭露血小板膜内α-颗粒外吐P-选择素与糖蛋白IIb/IIIa外化和变构的关联性，深化对血栓病理的认识。在临床层面，该研究会为抗血栓新药研究发现可进入临床前研究的优秀化合物。

Of the diseases, thrombosis has been known as a leading cause of morbidity and mortality around the world. There are two kinds of thrombi, which formed via two different pathways, in the patients. One is triggered by the exocytosis of P-selectin stored in the α-granule of the platelet. The other results from the eversion and the allosterism of GPIIb/IIIa. So far, all the known anti-thrombotic agents target either one or the other of the two pathways. Based on the mechanisms of both pathways, a strategy of designing novel anti-thrombotic agents that simultaneously inhibit the exocytosis of P-selectin and the allosterism of GPIIb/IIIa was established. Accordingly, a novel compound, N-(tetrahydroisoqunoline-3-carbonyl)-TARGD(F)F, was designed, of which the tetrahydroisoqunoline was for the binding at the active site pocket of P-selectin, the dipeptide TA was to form a transmembrane moiety and RGD(F)F was to occupy the binding sites of fibrinogen on GPIIb/IIIa. Preliminary experimental results prove that the lead compound N-(tetrahydroisoqunoline-3-carbonyl)-TARGD(F)F was capable of simultaneously inhibiting the exocytosis of P-selectin and the allosterism of GPIIb/IIIa, and consequently inhibiting the in vivo formation of thrombi. Further, molecular modelling studies was performed on its various analogs to optimize the lead compound. The modelling results show that the substitution of T with L or P, and the substitution of F with S or V will significantly improve the inhibiting activities of the lead compound. In this proposal, 8 optimized analogs of the lead compound will be synthesized, tested for their activities of inhibiting the exocytosis of P-selectin, inhibiting the allosterism of GPIIb/IIIa, inhibiting the aggregation of platelets, and inhibiting the in vivo formation of thrombsis. The preliminary results of the lead compound strongly support the feasibility and success of the following studies. Granting us the financial support is to ensure the discovery of novel effective anti-thrombotic agents and to benefit human beings suffer from thrombosis.