BTK/JAK3双靶点抑制剂的设计合成和生物活性评价OA北大核心CSTPCD
Design,synthesis and biological study of BTK/JAK3 dual-target inhibitors
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.
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.
岑丽芳;程铭;任玮杰;叶柳;王禄华;郭维博;张强;徐云根
中国药科大学药物化学系, 南京 210009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西安新通药物研究股份有限公司, 西安 710077
药学
类风湿性关节炎BTK抑制剂JAK3抑制剂双靶点抑制剂抗炎
rheumatoid arthritisBTK inhibitorJAK3 inhibitordual-target inhibitorsanti-inflammatory
《中国药科大学学报》 2024 (001)
73-86 / 14
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