Switching a Xanthine Oxidase Inhibitor to a Dual-Target Antagonist of P2Y1 and P2Y12 as an Oral Antiplatelet Agent with a Wider Therapeutic Window in Rats than Ticagrelor

ADP-mediated platelet aggregation is signaled through G protein-coupled receptors P2Y1 and P2Y12 on the platelet. The clinical effectiveness of inhibiting P2Y12 has been well established, and preclinical studies indicated that the inhibition of P2Y1 could provide equivalent antithrombotic efficacy as P2Y12 antagonists and reduce bleeding risks. On the basis of the 2-phenyl-1H-imidazole scaffold of our previously reported xanthine oxidase inhibitor WSJ-557, we first achieved the transition from the xanthine oxidase inhibitors to dual-target antagonists against P2Y1 and P2Y12. We described the structure–activity relationships of the 2-phenyl-1H-imidazole compounds, which led to the identification of the most potent antiplatelet agents, 24w and 25w, both showing a rapid onset of action in pharmacokinetic study. Furthermore, the rat model suggested that 24w demonstrated a wider therapeutic window than ticagrelor, displaying equivalent and dose-dependent antithrombotic efficacy with lower blood loss compared to ticagrelor at same oral dose. These results supported that 24w and 25w could be promising drug candidates.腺苷二磷酸（ADP）介导的血小板聚集，其信号转导依赖于血小板表面的G蛋白偶联受体（G protein-coupled receptor）P2Y1与P2Y12。靶向抑制P2Y12的临床疗效已得到充分证实；临床前研究显示，抑制P2Y1可获得与P2Y12拮抗剂相当的抗血栓疗效，同时降低出血风险。本研究以课题组此前报道的黄嘌呤氧化酶抑制剂（xanthine oxidase inhibitor）WSJ-557的2-苯基-1H-咪唑母核为基础，首次实现了从黄嘌呤氧化酶抑制剂到针对P2Y1与P2Y12的双靶点拮抗剂的结构转化。本研究阐明了2-苯基-1H-咪唑类化合物的构效关系（structure–activity relationships），最终筛选得到活性最优的抗血小板药物候选物24w与25w，二者在药代动力学研究中均展现出快速起效的特性。此外，大鼠模型实验结果表明，24w的治疗窗较替格瑞洛（ticagrelor）更为宽泛；在相同口服剂量下，其抗血栓疗效与替格瑞洛相当且呈剂量依赖性，同时出血量显著低于替格瑞洛。上述研究结果证实，24w与25w均为极具潜力的药物候选分子。