Novel Isoxazole Derivatives with Potent FXR Agonistic Activity Prevent Acetaminophen-Induced Liver Injury

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2019 Apr 19

PMID 30996771

Citations 7

Authors

Valentina Sepe

Silvia Marchiano

Claudia Finamore

Giuliana Baronissi

Francesco Saverio Di Leva

Adriana Carino

Michele Biagioli

Chiara Fiorucci

Chiara Cassiano

Maria Chiara Monti

Federica Del Gaudio

Ettore Novellino

Vittorio Limongelli

Stefano Fiorucci

Angela Zampella

Affiliations

Soon will be listed here.

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 that was orally active, and rescued mice from acute liver failure caused by acetaminophen overdose in a FXR-dependent manner.

Citing Articles

3D-QSAR and Molecular Dynamics Study of Isoxazole Derivatives to Identify the Structural Requirements for Farnesoid X Receptor (FXR) Agonists.

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Structure-Activity Relationship Studies of Trisubstituted Isoxazoles as Selective Allosteric Ligands for the Retinoic-Acid-Receptor-Related Orphan Receptor γt.

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Primary Biliary Cholangitis and Bile Acid Farnesoid X Receptor Agonists.

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