Synthesis andBiological Evaluation of Peripheral5HT_2B 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_2B) 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 IC₅₀ 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 CCl₄-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.