有机化学 ›› 2024, Vol. 44 ›› Issue (1): 259-276.DOI: 10.6023/cjoc202306001 上一篇    下一篇

研究论文

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

王婧怡a,b, 刘金羽c, 陈东升b, 陈华燕b, 谢欣*(), 南发俊a,b,c,*()   

  1. a 中国科学院大学 北京 100049
    b 中国科学院上海药物研究所 上海 201203
    c 南京中医药大学 南京 210023
  • 收稿日期:2023-06-01 修回日期:2023-07-18 发布日期:2023-09-08
  • 基金资助:
    国家自然科学基金(82003571)

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

Jingyi Wanga,b, Jinyu Liuc, Dongsheng Chenb, Huayan Chenb, Xin Xie(), Fajun Nana,b,c()   

  1. a University of Chinese Academy of Sciences, Beijing 100049
    b Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203
    c Nanjing University of Chinese Medicine, Nanjing 210023
  • Received:2023-06-01 Revised:2023-07-18 Published:2023-09-08
  • Contact: *E-mail: fjnan@simm.ac.cn; E-mail: xxie@simm.ac.cn
  • Supported by:
    National Natural Science Foundation of China(82003571)

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.

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

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-car- boxylic 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-chloro- quinolin-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.

Key words: cysteinyl leukotriene, cysteinyl leukotriene receptor 1 (CysLT1R), selective antagonists