Nature Communications (Jan 2024)

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

  • 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 Jong Lee,
  • Eun Young Lee,
  • Peter C. Goughnour,
  • Dooseop Kim,
  • In-Kyu Lee,
  • Rohit Loomba,
  • Hail Kim,
  • Jin Hee Ahn

DOI
https://doi.org/10.1038/s41467-024-44874-3
Journal volume & issue
Vol. 15, no. 1
pp. 1 – 12

Abstract

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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.