Zhao Zhichang, Wang Yeming, Tian Nana, Yan Hong, Wang Juan
Beijing Key Laboratory of Environmental and Viral Oncology, Faculty of Environment and Life, Beijing University of Technology Beijing 100124 P. R. China
Beijing Tide Pharmaceutical Co., Ltd, No.8 East Rongjing Street, Beijing Econnomi Technological Development Area (BDA) Beijing 100176 China.
RSC Med Chem. 2021 Jul 13;12(8):1414-1427. doi: 10.1039/d1md00128k. eCollection 2021 Aug 18.
Two series of novel derivatives of 8-azapurine and were designed as antiplatelet agents. Series and were amino derivatives and hydrazone derivatives of 8-azapurine, respectively. The compounds were synthesized in acceptable yields conventional procedures, including nucleophilic substitution, diazotization, and amination or hydrazonation with amino alcohol and 4,6-dichloropyrimidine as starting materials. To assess the ability of the synthesized compounds as antiplatelet agents, the ADP-induced platelet aggregation assay of Born was performed both and using ticagrelor as a reference control substance. The analysis of the structure-activity relationship and molecular docking were also discussed in detail. The results demonstrated that series and compounds exhibited antiplatelet activity and was the most active compound (IC = 0.20 μM) among the target compounds, being almost 4-fold better than ticagrelor (IC = 0.74 μM). For a preliminary assessment of the safety profile, a bleeding test (mouse tail) and a single-dose toxicity test were conducted. The use of compound resulted in a shorter bleeding time, less blood loss and lower acute toxicity compared to ticagrelor. In addition, a molecular docking study was performed to investigate the binding capacity and binding mode between and P2Y.
设计了两类新型的8-氮杂嘌呤衍生物作为抗血小板药物。系列Ⅰ和系列Ⅱ分别是8-氮杂嘌呤的氨基衍生物和腙衍生物。这些化合物采用常规方法合成，产率良好，以亲核取代、重氮化以及用氨基醇和4,6-二氯嘧啶进行胺化或腙化反应为起始步骤。为评估合成化合物作为抗血小板药物的能力，以替格瑞洛作为参比对照物质，在体外和体内均进行了博恩（Born）的ADP诱导的血小板聚集试验。还详细讨论了构效关系分析和分子对接。结果表明，系列Ⅰ和系列Ⅱ化合物均表现出抗血小板活性，且化合物Ⅱ是目标化合物中活性最高的（IC₅₀ = 0.20 μM），几乎比替格瑞洛（IC₅₀ = 0.74 μM）高4倍。为初步评估安全性，进行了出血试验（小鼠尾巴）和单剂量毒性试验。与替格瑞洛相比，化合物Ⅱ导致出血时间更短、失血量更少且急性毒性更低。此外，进行了分子对接研究以考察化合物Ⅱ与P2Y之间的结合能力和结合模式。
