摘要
目的合成新的替格瑞洛衍生物并研究其抗血小板聚集活性。方法将化合物替格瑞洛复杂的手性环丙基胺片段用相对简单的苯基烷胺或杂环烷胺类取代,设计合成了一系列非环丙基取代的替格瑞洛衍生物。以Boc保护的(R)-丙氨酸为原料,根据文献经多步反应得到中间体1;该中间体与4,6-二氯-2-正丙巯基嘧啶-5-胺缩合,环化生成三氮唑,最后再与各类胺缩合生成目标化合物。测定所有目标化合物抗兔血小板聚集的活性。结果共制得19个化合物,其化学结构由1 H-NMR和MS确证,且均未见文献报道。目标化合物表现出不同程度的抑制血小板聚集的活性,其中4f(IC_(50)=49.7μmol·L^(-1))活性明显高于阳性对照药替格瑞洛(IC50=71.5μmol·L^(-1)),有进一步研究价值。结论替格瑞洛分子的手性环丙基侧链并非活性必需基团,可作为结构优化的对象深入研究。
Objective To synthesize and evaluate the anti-platelet aggregation activity of ticagrelor analogues. Metholds A series of derivatives were designed and synthesized by replacing diflourophenyl cyclopropyl moiety of ticagrelor with two types of substituents, aryl alkyl groups and heteroaryl alkyl groups.The title compounds were obtained from Boc protected （R）-2-Aminopropionic acid through a series of reactions.Their inhibitory activity on ADP-induced platelet aggregation of rabbits was detected.Results Nineteen new derivatives were synthesized and confirmed by MS and 1H-NMR. Compound 4f exhibited higher activity with an IC50 of 49.7μmol·L^-1 than tieagrelor （71.5 μmol·L^-1） did,which could be consid- ered a lead compound for further modification.Conclusion The chiral cyclopropyl moiety of ticagrelor,which is not essential for the anti-platelet activity,can be taken as a target for structure optimization.
出处
《解放军药学学报》
CAS
CSCD
2017年第1期1-5,47,共6页
Pharmaceutical Journal of Chinese People's Liberation Army
基金
国家自然科学基金项目,No.21272270
关键词
替格瑞洛
抗血小板聚集
合成
构效关系
P2Y12受体
ticagrelor
anti-platelet aggregation
synthesis
structure-activity relationship
P2Y12 receptor
