新型选择性半胱氨酰白三烯受体1(CysLT1R)拮抗剂的设计合成及构效关系研究  

Design,Synthesis,and Structure-Activity Relationship of Novel Potent and Highly Selective Cysteinyl Leukotriene Receptor 1(CysLT1R)Antagonists

作　　者：王婧怡 刘金羽 陈东升 陈华燕 谢欣 南发俊[1,2] Wang Jingyi;Liu Jinyu;Chen Dongsheng;Chen Huayan;Xie Xin;Nan Fajun(University of Chinese Academy of Sciences,Beijing 100049;Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203;Nanjing University of Chinese Medicine,Nanjing 210023)

机构地区：[1]中国科学院大学,北京100049 [2]中国科学院上海药物研究所,上海201203 [3]南京中医药大学,南京210023

出　　处：《有机化学》2024年第1期259-276,共18页Chinese Journal of Organic Chemistry

基　　金：国家自然科学基金(No.82003571)资助项目.

摘　　要：半胱氨酰白三烯(CysLTs)是炎症脂介质,其受体(CysLTsR)在哮喘、过敏性鼻炎和癌症等疾病的发生发展中发挥重要作用.已发现3-取代1H-吲哚-2-羧酸衍生物具有半胱氨酰白三烯受体1(CysLT1R)拮抗活性,但较差的溶解度限制了其进一步研究.基于已有研究基础继续进行结构优化,设计合成了多个系列化合物,其中3-{2-[(1E)-3-({3-[(1E)-2-(7-氯喹啉-2-基)乙烯基]苯基}氨基)-3-氧亚基丙-1-烯基]苯基}丙酸(T9)展现出良好的选择性CysLT1受体拮抗活性和改善的溶解度,其IC50值为(0.0066±0.0023)μmol/L,在水中溶解度为4.16×10^(-5) g/mL.Cysteinyl leukotrienes(CysLTs)are lipid mediators of inflammation,and their receptors(CysLTsR)play an essential role in asthma,allergic rhinitis,cancer,and other diseases.According to earlier studies,3-substituted 1H-indole-2-carboxylic acid derivatives displayed selective cysteinyl leukotriene receptor 1(CysLT1R)antagonistic activity,while their poor water solubility restricted their further evaluation.Hence,structural optimization was continued and multiple series of compounds were designed and synthesized based on existing research foundations.Among them,3-(2-((E)-3-((3-((E)-2-(7-chloroquinolin-2-yl)vinyl)phenyl)amino)-3-oxoprop-1-en-1-yl)phenyl)propanoic acid(T9)exhibits good selective CysLT1 receptor antagonistic activity and improved solubility,with IC50 value of(0.0066±0.0023)μmol/L and water solubility of 4.16×10-5 g/mL.

关 键 词：半胱氨酰白三烯 半胱氨酰白三烯受体1(CysLT1R) 选择性拮抗剂 

分 类 号：TQ460.1[化学工程—制药化工]