Discovery of 7-alkoxybenzofurans as PDE4 inhibitors with hepatoprotective activity in D-GalN/LPS-induced hepatic sepsis.
Eur J Med Chem
; 275: 116576, 2024 Sep 05.
Article
in En
| MEDLINE
| ID: mdl-38861808
ABSTRACT
Sepsis can quickly result in fatality for critically ill individuals, while liver damage can expedite the progression of sepsis, necessitating the exploration of new strategies for treating hepatic sepsis. PDE4 has been identified as a potential target for the treatment of liver damage. The scaffold hopping of lead compounds FCPR16 and Z19153 led to the discovery of a novel 7-methoxybenzofuran PDE4 inhibitor 4e, demonstrating better PDE4B (IC50 = 10.0 nM) and PDE4D (IC50 = 15.2 nM) inhibitor activity as a potential anti-hepatic sepsis drug in this study. Compared with FCPR16 and Z19153, 4e displayed improved oral bioavailability (F = 66 %) and longer half-life (t1/2 = 2.0 h) in SD rats, which means it can be more easily administered and has a longer-lasting effect. In the D-GalN/LPS-induced liver injury model, 4e exhibited excellent hepatoprotective activity against hepatic sepsis by decreasing ALT and AST levels and inflammatory infiltrating areas.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Benzofurans
/
Sepsis
/
Phosphodiesterase 4 Inhibitors
/
Galactosamine
Limits:
Animals
/
Humans
/
Male
Language:
En
Journal:
Eur J Med Chem
Year:
2024
Document type:
Article
Country of publication:
Francia