Anti-hepatic fibrosis agent 3 is an orally active anti-hepatic fibrosis compound targeting Cathepsin D. Anti-hepatic fibrosis agent 3 shows an IC50 of 53.18 μM against COL1A1-promoter and a K d of 8.86 μM for binding to Cathepsin D. Anti-hepatic fibrosis agent 3 directly binds to and promotes the degradation of Cathepsin D, with no significant effect on Cathepsin B or Cathepsin L. Anti-hepatic fibrosis agent 3 inhibits hepatic stellate cell activation and reduces extracellular matrix deposition and inflammatory cytokine expression. Anti-hepatic fibrosis agent 3 exhibits remarkable anti-fibrotic activity in rat BDL and mouse CDAHFD-induced hepatic fibrosis models. Anti-hepatic fibrosis agent 3 can be used for the study of hepatic fibrosis [1].
In Vivo, Anti-hepatic fibrosis agent 3 (100-200 mg/kg; p.o.; daily; 14 days) dose-dependently alleviates BDL-induced hepatic fibrosis and inflammation in male Sprague-Dawley rats, with significant reductions in serum liver injury markers, collagen deposition, fibrotic and inflammatory biomarker expression, and Cathepsin D levels at doses of 100 mg/kg and 200 mg/kg[1]. Anti-hepatic fibrosis agent 3 (100-200 mg/kg; p.o.; daily; 4 weeks) dose-dependently ameliorates CDAHFD-induced metabolic hepatic fibrosis and inflammation in C57BL/6 mice, with significant improvements in serum liver injury markers, reductions in collagen deposition, fibrotic and inflammatory biomarker expression, and Cathepsin D levels at doses of 100 mg/kg and 200 mg/kg[1].
In Vitro, Anti-hepatic fibrosis agent 3 (compound 9a) potently inhibits COL1A1-promoter activity in LX-2 cells with an IC50 of 53.18 μM and a selectivity index of 3.60[1]. Anti-hepatic fibrosis agent 3 (20-80 μM; 24 h) inhibits fibrogenic marker proteins (COL1A1, fibronectin, α-SMA, p-Smad2) and suppresses fibrosis-related gene mRNA levels (COL1A1, fibronectin, TGFB1, MMP2, ACTA2, TIMP1) TGFβ1-induced LX-2 cells, and reduces fibrogenic protein expression in mouse hepatic stellate cells (mHSC) in a concentration-dependent manner[1]. Anti-hepatic fibrosis agent 3 (20-80 μM; 24 h) dose-dependently downregulates pro-Cathepsin D and Cathepsin D protein levels with no effect on Cathepsin B and Cathepsin L in LX-2 and mHSC cells, and decreases inflammatory protein expression (IL-1β, caspase-1) in Lipopolysaccharides -stimulated LX-2 and mHSC cells[1]. Anti-hepatic fibrosis agent 3 (80 μM; 6-48 h) accelerates the degradation of pro-Cathepsin D and Cathepsin D in Cycloheximide -pretreated LX-2 cells<[1].
References:
[1]. Lv M, et al. Design, Synthesis, and Mechanistic Evaluation of l-Theanine Derivatives Targeting Cathepsin D for Anti-Hepatic Fibrosis. J Med Chem. 2026;69(4):4493-4511.
In Vivo, Anti-hepatic fibrosis agent 3 (100-200 mg/kg; p.o.; daily; 14 days) dose-dependently alleviates BDL-induced hepatic fibrosis and inflammation in male Sprague-Dawley rats, with significant reductions in serum liver injury markers, collagen deposition, fibrotic and inflammatory biomarker expression, and Cathepsin D levels at doses of 100 mg/kg and 200 mg/kg[1]. Anti-hepatic fibrosis agent 3 (100-200 mg/kg; p.o.; daily; 4 weeks) dose-dependently ameliorates CDAHFD-induced metabolic hepatic fibrosis and inflammation in C57BL/6 mice, with significant improvements in serum liver injury markers, reductions in collagen deposition, fibrotic and inflammatory biomarker expression, and Cathepsin D levels at doses of 100 mg/kg and 200 mg/kg[1].
In Vitro, Anti-hepatic fibrosis agent 3 (compound 9a) potently inhibits COL1A1-promoter activity in LX-2 cells with an IC50 of 53.18 μM and a selectivity index of 3.60[1]. Anti-hepatic fibrosis agent 3 (20-80 μM; 24 h) inhibits fibrogenic marker proteins (COL1A1, fibronectin, α-SMA, p-Smad2) and suppresses fibrosis-related gene mRNA levels (COL1A1, fibronectin, TGFB1, MMP2, ACTA2, TIMP1) TGFβ1-induced LX-2 cells, and reduces fibrogenic protein expression in mouse hepatic stellate cells (mHSC) in a concentration-dependent manner[1]. Anti-hepatic fibrosis agent 3 (20-80 μM; 24 h) dose-dependently downregulates pro-Cathepsin D and Cathepsin D protein levels with no effect on Cathepsin B and Cathepsin L in LX-2 and mHSC cells, and decreases inflammatory protein expression (IL-1β, caspase-1) in Lipopolysaccharides -stimulated LX-2 and mHSC cells[1]. Anti-hepatic fibrosis agent 3 (80 μM; 6-48 h) accelerates the degradation of pro-Cathepsin D and Cathepsin D in Cycloheximide -pretreated LX-2 cells<[1].
References:
[1]. Lv M, et al. Design, Synthesis, and Mechanistic Evaluation of l-Theanine Derivatives Targeting Cathepsin D for Anti-Hepatic Fibrosis. J Med Chem. 2026;69(4):4493-4511.