化学
哈卡特
促炎细胞因子
银屑病
胺气处理
激酶
药品
药理学
立体化学
结构-活动关系
生物化学
炎症
体外
免疫学
医学
有机化学
作者
Yi Zhu,Yuxiang Ma,Weidong Zu,Jianing Song,Hua Wang,You Zhong,Hongmei Li,Yanmin Zhang,Qianqian Gao,Bo Kong,Junyu Xu,Fei Jiang,Xinren Wang,Shuwen Li,Chenhe Liu,Haichun Liu,Tao Lü,Yadong Chen
标识
DOI:10.1021/acs.jmedchem.0c00055
摘要
A series of N-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine derivatives with NF-κB inducing kinase (NIK) inhibitory activity were obtained through structure-based drug design and synthetic chemistry. Among them, 4-(3-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-4-morpholinophenyl)-2-(thiazol-2-yl)but-3-yn-2-ol (12f) was identified as a highly potent NIK inhibitor, along with satisfactory selectivity. The pharmacokinetics of 12f and its ability to inhibit interleukin 6 secretion in BEAS-2B cells were better than compound 1 developed by Amgen. Oral administration of different doses of 12f in an imiquimod-induced psoriasis mouse model showed effective alleviation of psoriasis, including invasive erythema, swelling, skin thickening, and scales. The underlying pathological mechanism involved attenuation of proinflammatory cytokine and chemokine gene expression, and the infiltration of macrophages after the treatment of 12f. This work provides a foundation for the development of NIK inhibitors, highlighting the potential of developing NIK inhibitors as a new strategy for the treatment of psoriasis.
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