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Novel Isoxazole Derivatives with Potent FXR Agonistic Activity Prevent Acetaminophen-Induced Liver Injury
Valentina Sepe
1 ,
Silvia Marchianò
2 ,
Claudia Finamore
1 ,
Giuliana Baronissi
1 ,
Francesco Saverio Di Leva
1 ,
Adriana Carino
2 ,
Michele Biagioli
2 ,
Chiara Fiorucci
2 ,
Chiara Cassiano
3 ,
Maria Chiara Monti
3 ,
Federica del Gaudio
3 ,
Ettore Novellino
1 ,
Vittorio Limongelli
1
,
4 ,
Stefano Fiorucci
2 ,
Angela Zampella
1
December 12 2018
December 12 2018
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Abstract
Acetaminophen misuse is a leading cause of acute liver failure and liver transplantation
for which therapy is poorly effective. FXR ligands have shown effective in reducing
liver injury in several experimental and clinical settings. In this Letter, we have
elaborated on the structure of GW4064, the first nonsteroidal agonist for FXR, to
identify novel isoxazoles endowed with FXR agonistic activity and improved ADME properties.
The pharmacological characterization and molecular docking studies for the structure-activity
rationalization allowed the identification of several FXR agonists with nanomolar
potency in transactivation and SRC-1 recruitment assays. This characterization resulted
in the identification of a potent FXR agonist, compound 20 that was orally active,
and rescued mice from acute liver failure caused by acetaminophen overdose in a FXR-dependent
manner.