2. Academic Validation
  3. Discovery and Optimization of Novel Nonbile Acid FXR Agonists as Preclinical Candidates for the Treatment of Inflammatory Bowel Disease

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

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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