2. Academic Validation
  3. Synthesis and Biological Evaluation of Peripheral 5HT2B Antagonists for Liver Fibrosis

Synthesis and Biological Evaluation of Peripheral 5HT2B Antagonists for Liver Fibrosis

  • J Med Chem. 2025 Mar 6. doi: 10.1021/acs.jmedchem.4c03003.
Jihyeon Yoon 1,  Won-Il Choi 2 3,  Won Hee Lee 3 4,  Gwi Bin Lee 1,  Byeong Wook Choi 1,  Pyeongkeun Kim 1,  Yerim Heo 1,  Dong Gun Kim 1,  Hyeon Ah Kim 1,  Myung Ae Bae 5,  Seong Soon Kim 5,  Eun Young Lee 6,  Chang-Myung Oh 7,  Hyeok Jae Lee 1,  Hyun Woo Kim 1 8,  Wan Namkung 9,  Hail Kim 3 4,  Jin Hee Ahn 1 6
Affiliations

Affiliations

  • 1 Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea.
  • 2 Department of Physiology, Jeonbuk National University Medical School, Jeonju 54907, Republic of Korea.
  • 3 Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea.
  • 4 Biomedical Research Center, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea.
  • 5 Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea.
  • 6 JD Bioscience Inc., TJS Knowledge Industrial Center, Suite 801, 208 Beon-gil Cheomdangwagi-ro, Buk-gu, Gwangju 61011, Republic of Korea.
  • 7 Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea.
  • 8 Center for Quantum Information, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea.
  • 9 College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983, Republic of Korea.
PMID: 40048549 DOI: 10.1021/acs.jmedchem.4c03003
Abstract

Liver fibrosis is characterized by an excessive accumulation of extracellular matrix components, leading to the distortion of liver architecture and function. Recent studies have shown that antagonizing 5-hydroxytryptamine receptor 2B (5HT2B) stimulates the Apoptosis of activated hepatic stellate cells and inhibits their proliferation while concurrently regressing hepatocyte proliferation. In this study, we present compound 19c, which demonstrates promising efficacy both in vitro and in vivo. 19c showed robust in vitro activity with an IC50 value of 1.09 nM and limited blood-brain barrier penetration. Furthermore, 19c did not significantly inhibit hERG and Cytochrome P450 enzymes. 19c markedly reduced fibrotic deposition, with a decrease in fibrosis stage and area in the CCl4-induced liver fibrosis mouse model. Additionally, treatment with 19c led to downregulation of key fibrosis-related genes, including α-SMA, Timp1, Col1a1, and Col3a1. Taken together, these results suggest that 19c has the potential to be a novel antifibrotic agent.

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