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

ACS Med Chem Lett. 2018 Dec 6;10(4):407-412. doi: 10.1021/acsmedchemlett.8b00423.

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

Affiliations

1 Department of Pharmacy, University of Naples "Federico II", via D. Montesano 49, 80131 Naples, Italy.
2 Department of Surgery and Biomedical Sciences, Nuova Facoltà di Medicina, Perugia, Italy.
3 Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 132, 84084 Fisciano, Salerno, Italy.
4 Università della Svizzera Italiana (USI), Faculty of Biomedical Sciences, Institute of Computational Science - Center for Computational Medicine in Cardiology, Via G. Buffi 13, CH-6900 Lugano, Switzerland.

PMID: 30996771 DOI: 10.1021/acsmedchemlett.8b00423

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.

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