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Discovery of a peripheral 5HT2A antagonist as a clinical candidate for metabolic dysfunction-associated steatohepatitis

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  • Haushabhau S. Pagire

    (Gwangju Institute of Science and Technology
    TJS Knowledge Industrial Center Suite 801)

  • Suvarna H. Pagire

    (Gwangju Institute of Science and Technology
    TJS Knowledge Industrial Center Suite 801)

  • Byung-kwan Jeong

    (Korea Advanced Institute of Science and Technology)

  • Won-Il Choi

    (Korea Advanced Institute of Science and Technology)

  • Chang Joo Oh

    (Kyungpook National University School of Medicine)

  • Chae Won Lim

    (Kyungpook National University Hospital)

  • Minhee Kim

    (Gwangju Institute of Science and Technology)

  • Jihyeon Yoon

    (Gwangju Institute of Science and Technology)

  • Seong Soon Kim

    (Korea Research Institute of Chemical Technology)

  • Myung Ae Bae

    (Korea Research Institute of Chemical Technology)

  • Jae-Han Jeon

    (Kyungpook National University School of Medicine
    Kyungpook National University Chilgok Hospital)

  • Sungmin Song

    (TJS Knowledge Industrial Center Suite 801)

  • Hee Jong Lee

    (TJS Knowledge Industrial Center Suite 801)

  • Eun Young Lee

    (TJS Knowledge Industrial Center Suite 801)

  • Peter C. Goughnour

    (TJS Knowledge Industrial Center Suite 801)

  • Dooseop Kim

    (TJS Knowledge Industrial Center Suite 801)

  • In-Kyu Lee

    (Kyungpook National University School of Medicine
    Kyungpook National University Hospital)

  • Rohit Loomba

    (University of California at San Diego)

  • Hail Kim

    (Korea Advanced Institute of Science and Technology
    Korea Advanced Institute of Science and Technology (KAIST))

  • Jin Hee Ahn

    (Gwangju Institute of Science and Technology
    TJS Knowledge Industrial Center Suite 801)

Abstract

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is currently the leading cause of chronic liver disease worldwide. Metabolic Dysfunction-Associated Steatohepatitis (MASH), an advanced form of MASLD, can progress to liver fibrosis, cirrhosis, and hepatocellular carcinoma. Based on recent findings by our team that liver 5HT2A knockout male mice suppressed steatosis and reduced fibrosis-related gene expression, we developed a peripheral 5HT2A antagonist, compound 11c for MASH. It shows good in vitro activity, stability, and in vivo pharmacokinetics (PK) in rats and dogs. Compound 11c also shows good in vivo efficacy in a diet-induced obesity (DIO) male mice model and in a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) male mice model, effectively improving histologic features of MASH and fibrosis. According to the tissue distribution study using [14C]-labeled 11c, the compound was determined to be a peripheral 5HT2A antagonist. Collectively, first-in-class compound 11c shows promise as a therapeutic agent for the treatment of MASLD and MASH.

Suggested Citation

  • Haushabhau S. Pagire & Suvarna H. Pagire & Byung-kwan Jeong & Won-Il Choi & Chang Joo Oh & Chae Won Lim & Minhee Kim & Jihyeon Yoon & Seong Soon Kim & Myung Ae Bae & Jae-Han Jeon & Sungmin Song & Hee , 2024. "Discovery of a peripheral 5HT2A antagonist as a clinical candidate for metabolic dysfunction-associated steatohepatitis," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-44874-3
    DOI: 10.1038/s41467-024-44874-3
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    1. Chang-Myung Oh & Jun Namkung & Younghoon Go & Ko Eun Shong & Kyuho Kim & Hyeongseok Kim & Bo-Yoon Park & Ho Won Lee & Yong Hyun Jeon & Junghan Song & Minho Shong & Vijay K. Yadav & Gerard Karsenty & S, 2015. "Regulation of systemic energy homeostasis by serotonin in adipose tissues," Nature Communications, Nature, vol. 6(1), pages 1-12, November.
    2. Ingmar Mederacke & Christine C. Hsu & Juliane S. Troeger & Peter Huebener & Xueru Mu & Dianne H. Dapito & Jean-Philippe Pradere & Robert F. Schwabe, 2013. "Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology," Nature Communications, Nature, vol. 4(1), pages 1-11, December.
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