Discovery and Optimization of Novel Nonbile Acid FXR Agonists as Preclinical Candidates for the Treatment of Inflammatory Bowel Disease

  • J Med Chem. 2024 Apr 11;67(7):5642-5661. doi: 10.1021/acs.jmedchem.3c02304.
Yuan Li  1 ,  Tingting Xu  2 ,  Yue Zhao  2 ,  Hui Zhang  2 ,  Zesheng Liu  2 ,  Hao Wang  1 ,  Chaoying Huang  3 ,  Zhihao Shu  1 ,  Lixin Gao  1 ,  Rongrong Xie  1 ,  Tingying Jiao  1 ,  Dan Zhang  1 ,  Dong Zhang  1 ,  Xuewu Liang  1 ,  Yi Zang  4 ,  Yili Sun  1  5 ,  Hong Liu  1  2  6 ,  Jia Li  1  2  5  6 ,  Yu Zhou  1  2  6
Affiliations
  • 1. Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 2. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
  • 3. School of Medicine, Shanghai University, Shanghai, 200444, China.
  • 4. Lingang laboratory, Shanghai, 201203, China.
  • 5. Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, China.
  • 6. School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China.
PMID: 38547240 DOI: 10.1021/acs.jmedchem.3c02304
Abstract

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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