BTK/JAK3双靶点抑制剂的设计合成和生物活性评价
Design,synthesis and biological study of BTK/JAK3 dual-target inhibitors
岑丽芳 1程铭 1任玮杰 1叶柳 1王禄华 1郭维博 2张强 3徐云根1
作者信息
- 1. 中国药科大学药物化学系, 南京 210009
- 2. 中国药科大学药物化学系, 南京 210009;西安新通药物研究股份有限公司, 西安 710077
- 3. 西安新通药物研究股份有限公司, 西安 710077
- 折叠
摘要
以课题组前期发现的XL-12为先导化合物,通过末端苯环的结构修饰,进一步提高化合物的抗炎活性.设计并合成了 12个目标化合物.所有目标化合物的结构经1H NMR、13C NMR和HRMS确证.体外活性测试结果显示大部分化合物对布鲁顿型酪氨酸激酶(Bruton's tyrosine,BTK)和Janus激酶 3(JAK3)具有较好的酶抑制活性,化合物I-3对Daudi细胞和BaF3-JAK3细胞显示中等的细胞增殖抑制活性.在体外抗炎活性评价中,化合物I-3能有效抑制炎症因子IL-6的产生.此外,在小鼠二甲苯致耳廓肿胀模型中,化合物I-3显示出优于阳性药依鲁替尼(ibrutinib)的抗炎活性.
Abstract
In the present study,the compound XL-12 from our previous work was utilized as a lead compound.Through the optimization of the terminal phenyl ring,12 target compounds were designed and synthesized.The structures of all target compounds were confirmed by 1H NMR,13C NMR,and H RMS.In vitro enzyme activity assay showed that most compounds demonstrated significant inhibitory activity toward Bruton's tyrosine kinase(BTK)and Janus kinase 3(JAK3).Among them,compound I-3 exhibited moderate cell proliferation inhibitory activity toward Daudi cells and BaF3-JAK3 cells.In the evaluation of anti-inflammatory activity in vitro,compound I-3 could effectively inhibit the production of inflammatory factors IL-6;besides,it exhibited superior anti-inflammatory activity compared to ibrutinib in xylene-induced ear swelling model in mice.
关键词
类风湿性关节炎/BTK抑制剂/JAK3抑制剂/双靶点抑制剂/抗炎Key words
rheumatoid arthritis/BTK inhibitor/JAK3 inhibitor/dual-target inhibitors/anti-inflammatory引用本文复制引用
出版年
2024
国家科技期刊平台
NSTL
万方数据