Design, Synthesis, Activity Evaluation Of Thienopyridine Derivatives And Its Pharmacophore Model

As people's living standard keeps on going up and the ratio of high-fat food in diets increased, cardiovascular disease (CVD) is rapidly emerging as the most important cause of mortality in the whole world. Thrombosis is considered to be the major complication and reason of causing death of CVD and atherosclerosis in known etiopathogenesis.Thienopyridines, antagonists of the platelet P2Y₁₂ receptor, are the most effective drugs to prevent thrombus in clinical. Because of a number of limitations associated with drugs in the market novel antiplatelet thienopyridines are under research.Structure of clopidogrel was determined to be the initial structure and the thienopyridine mother nucleus was kept by the study of drugs in the market and reported thienopyridines. Seven novel classes of thienopyridine derivatives (237 in total) were designed by the method of isostere and so on. P2Y₁₂, receptor of thienopyridines belongs to G-protein-coupled receptor, its experimental 3D structure has not been got yet. In this paper, its 3D structure was modelled by homology modelling and the receptor-ligand interaction was predicted. 115 compounds were selected to be synthesized from designed 237 compounds by virtual screening using the modelled complex. Finally, 110 compounds were succeedly synthesized, their in vivo antiplatelet aggregation activities were evaluated and initial structure-activity relationship was studied. Compounds C1, C12, C13, D1, E1, F7, F8, F18, G28, G34 and G49 exhibited more potent inhibitory activity than other compounds synthesized and their antithrombotic effect was also evaluated. These 11 compounds were confirmed to have antithrombotic effect by inhibition of platelet aggregation. We think these 11 compounds have the potential to be drugs.To study the 3D bind mode of thienopyridine and its P2Y₁₂ receptor further and produce theoretical guide for designing novel derivatives, 11 compounds with highest activity were selected to construct pharmacophore models. These models will produce theoretical bases for drug design, strcture optimization and virtual screening.