法尼甾体X受体
炎症性肠病
前药
胆汁酸
核受体
化学
药理学
炎症
肠上皮
药品
药物代谢
疾病
内科学
医学
上皮
生物化学
转录因子
基因
病理
作者
Yuan Li,Tingting Xu,Yue Zhao,Hui Zhang,Zesheng Liu,Hao Wang,Chao-Ying Huang,Zhihao Shu,Lixin Gao,Rongrong Xie,Tingying Jiao,Dan Zhang,Dong Zhang,Xuewu Liang,Yi Zang,Yili Sun,Hong Liu,Jia Li,Yu Zhou
标识
DOI:10.1021/acs.jmedchem.3c02304
摘要
Inflammatory bowel disease (IBD) is a multifactorial chronic inflammation of the intestine and has become a global public health concern. A farnesoid X receptor (FXR) was recently reported to play a key role in hepatic-intestinal circulation, intestinal metabolism, immunity, and microbial regulation, and thus, it becomes a promising therapeutic target for IBD. In this study, we identified a series of nonbile acid FXR agonists, in which 33 novel compounds were designed and synthesized by the structure-based drug design strategy from our previously identified hit compound. Compound 33 exhibited a potent FXR agonistic activity, high intestinal distribution, good anti-inflammatory activity, and the ability to repair the colon epithelium in a DSS-induced acute enteritis model. Based on the results of RNA-seq analysis, we further investigated the therapeutic potential of the combination of compound 33 with 5-ASA. Overall, the results indicated that compound 33 is a promising drug candidate for IBD treatment.
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