Synthesis and Biological Evaluation of Peripheral 5HT<sub>2B</sub> Antagonists for Liver Fibrosis
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 (5HT<sub>2B</sub>) stimulates the apoptosis of activated hepatic stellate cells and inhibits their proliferation while concurrently regressing hepatocyte proliferation. In this study, we present compound <b>19c</b>, which demonstrates promising efficacy both <i>in vitro</i> and <i>in vivo</i>. <b>19c</b> showed robust <i>in vitro</i> activity with an IC<sub>50</sub> value of 1.09 nM and limited blood-brain barrier penetration. Furthermore, <b>19c</b> did not significantly inhibit hERG and cytochrome P450 enzymes. <b>19c</b> markedly reduced fibrotic deposition, with a decrease in fibrosis stage and area in the CCl<sub>4</sub>-induced liver fibrosis mouse model. Additionally, treatment with <b>19c</b> led to downregulation of key fibrosis-related genes, including α-SMA, Timp1, Col1a1, and Col3a1. Taken together, these results suggest that <b>19c</b> has the potential to be a novel antifibrotic agent.
Authors
- Jihyeon Yoon
- Hail Kim (ORCID: https://orcid.org/0000-0002-6652-1349)
- Seong Soon Kim (ORCID: https://orcid.org/0000-0002-4762-8693)
- Jin Hee Ahn (ORCID: https://orcid.org/0000-0002-6957-6062)
- Won‐Il Choi (ORCID: https://orcid.org/0000-0002-4837-0436)
- Yooun Heo (ORCID: https://orcid.org/0000-0003-4602-2048)
- W. Namkung (ORCID: https://orcid.org/0000-0002-1480-7433)
- Chang‐Myung Oh (ORCID: https://orcid.org/0000-0001-6681-4478)
- Hyeon Ah Kim
- Hyeok Jae Lee
- Dong‐Gun Kim
- Gwi Bin Lee (ORCID: https://orcid.org/0000-0001-9100-256X)
- Myung Ae Bae (ORCID: https://orcid.org/0000-0002-2997-5018)
- Byeong Wook Choi
- Hyun Woo Kim (ORCID: https://orcid.org/0000-0002-2472-2046)
- Eun Young Lee (ORCID: https://orcid.org/0000-0002-4513-9888)
- Won Hee Lee (ORCID: https://orcid.org/0000-0003-3991-3870)
- Pyeongkeun Kim
Institutions
- Korea Advanced Institute of Science and Technology (KR)
- Yonsei University (KR)
- Gwangju Institute of Science and Technology (KR)
- Quantum (Australia) (AU)
- Drug Discovery Laboratory (Norway) (NO)
- Korea Research Institute of Chemical Technology (KR)
- Korea Institute of Science and Technology (KR)
- Jeonbuk National University (KR)
- Korea Institute of Science & Technology Information (KR)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-03-06
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c03003
- Citations
- 2
- Primary Topic
- Liver Disease Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 2.71
Funders
- National Research Foundation of Korea