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

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    Discovery and Optimization of Novel Nonbile Acid FXR Agonists as Preclinical Candidates for the Treatment of Inflammatory Bowel Disease
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    • Yuan Li
      Yuan Li
      Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
      More by Yuan Li
    • Tingting Xu
      Tingting Xu
      School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China
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    • Yue Zhao
      Yue Zhao
      School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China
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    • Hui Zhang
      Hui Zhang
      School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China
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    • Zesheng Liu
      Zesheng Liu
      School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China
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    • Hao Wang
      Hao Wang
      Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
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    • Chaoying Huang
      Chaoying Huang
      School of Medicine, Shanghai University, Shanghai, 200444, China
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    • Zhihao Shu
      Zhihao Shu
      Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
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    • Lixin Gao
      Lixin Gao
      Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
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    • Rongrong Xie
      Rongrong Xie
      Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
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    • Tingying Jiao
      Tingying Jiao
      Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
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    • Dan Zhang
      Dan Zhang
      Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
      More by Dan Zhang
    • Dong Zhang
      Dong Zhang
      Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
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    • Xuewu Liang
      Xuewu Liang
      Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
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    • Yi Zang
      Yi Zang
      Lingang laboratory, Shanghai, 201203, China
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    • Yili Sun*
      Yili Sun
      Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
      Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, China
      * E-mail: [email protected]. Tel: +86-21-50806600.
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    • Hong Liu*
      Hong Liu
      Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
      School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China
      School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China
      *E-mail: [email protected]. Tel: +86-21-50807042.
      More by Hong Liu
      Orcidhttps://orcid.org/0000-0003-3685-6268
    • Jia Li*
      Jia Li
      Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
      School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China
      Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, China
      School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China
      *E-mail: [email protected]. Tel: +86-21-50806600.
      More by Jia Li
    • Yu Zhou*
      Yu Zhou
      Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
      School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China
      School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China
      *E-mail: [email protected]. Tel: +86-21-68077970.
      More by Yu Zhou
      Orcidhttps://orcid.org/0000-0002-7684-2939
    Other Access OptionsSupporting Information (5)

    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2024, 67, 7, 5642–5661
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    https://doi.org/10.1021/acs.jmedchem.3c02304
    Published March 28, 2024
    Copyright © 2024 American Chemical Society
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    Abstract

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    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.

    Copyright © 2024 American Chemical Society

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    Supporting Information

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jmedchem.3c02304.

    • 1H NMR, 13C NMR, and HPLC spectra of all target compounds and supplemental figures and tables (PDF)

    • Molecular formula stings (CSV)

    • FXR protein PDB (PDB)

    • FXR protein PDB (PDB)

    • FXR protein PDB (PDB)

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    Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

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    This article is cited by 3 publications.

    1. Yongjian Hu, Mingming Gao, Jiajin Chenghuang, Rui Bao. Insights into the gut-liver axis: mechanisms and emerging therapies in hepatocellular carcinoma. Frontiers in Pharmacology 2025, 16 https://doi.org/10.3389/fphar.2025.1595853
    2. Li Zhang, Yaqiong Chen, Weihua Li. Computational Insights into the Interactions of Farnesoid X Receptor with Fargesone A, a Natural Product from Magnolia fargesii. Chemical Research in Chinese Universities 2025, 41 (1) , 146-154. https://doi.org/10.1007/s40242-024-4210-6
    3. Xing Chen, Yan Lou, Feilong Zhou, Daxing Shi, Xinhua Liu, Fangbiao Tao. Identification of novel indolinone derivatives as CTSC inhibitors to treat inflammatory bowel disease by modulating inflammatory factors. European Journal of Medicinal Chemistry 2024, 280 , 116914. https://doi.org/10.1016/j.ejmech.2024.116914
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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2024, 67, 7, 5642–5661
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.jmedchem.3c02304
    Published March 28, 2024
    Copyright © 2024 American Chemical Society
    Request reuse permissions

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