新型喹喔啉类蛋白酶激活受体4(PAR4)拮抗剂的设计、合成及抗血小板活性研究  

Design, synthesis and antiplatelet activity evaluation of novel quinoxaline antagonists of protease activated receptor 4(PAR4)

作　　者：谢柔洁 刘尚德[1] 袁铎[1] 李杉杉[1] 朱雄[1] XIE Rou-jie;LIU Shang-de;YUAN Duo;LI Shan-shan;ZHU Xiong(China Pharmaceutical University,Nanjing 210009,China)

机构地区：[1]中国药科大学,江苏南京210009

出　　处：《药学学报》2022年第3期731-740,共10页Acta Pharmaceutica Sinica

摘　　要：基于文献报道的喹喔啉类PAR4抑制剂,本文设计合成了25个新型具有抗血小板活性的喹喔啉类化合物,结构通过^(1)H NMR、^(13)C NMR、MS进行确证。对化合物进行抗血小板活性评价、构效关系研究和FLIPER钙流检测。结果表明,化合物14a、14g、13i、13p的活性较好且都具有PAR4选择性。特别是化合物14g (IC_(50)=0.26μmol·L^(-1)),相对先导化合物A (IC_(50)=1.73μmol·L^(-1))活性提高了6.7倍。本文发现的以2,3-二氢萘[2,3-g]二噁唑[1,4]喹喔啉和[1,3]二噁唑[4,5-g]喹喔啉为母核的衍生物是一类具有潜力的新型抗血小板化合物,值得进一步研究,以开发出高效的新型PAR4选择性拮抗剂。Twenty-five compounds of novel quinoxaline-based scaffold with antiplatelet activity were designed and synthesized on the basis of previous quinoxaline analogues, and the structures were confirmed by ^(1)H NMR,^(13)C NMR, and MS. The antiplatelet activity was evaluated, structure-activity relationship(SAR) study was summarized and the selectivity of PAR4 was confirmed by calcium mobilization assays. It was indicated that compound 14a, 14g, 13i, 13p showed moderate activity against PAR4, especially, the activity of compound 14 g(IC_(50)= 0.26 μmol·L^(-1)) was 6.7 times than the lead compound A(IC_(50)= 1.73 μmol·L^(-1)). Therefore, 2,3-dihydro-[1,4]dioxino[2, 3-g]quinoxaline and [1, 3]dioxolo[4, 5-g]quinoxaline derivatives are promising compounds for the discovery of novel antiplatelet agents. It is worthy of further research to develop highly effective and selective PAR4 antagonists.

关 键 词：喹喔啉母核 PAR4拮抗剂 选择性 抗血小板活性 

分 类 号：R914[医药卫生—药物化学]