Expanding the library of 1,2,4-oxadiazole derivatives

Finamore, Claudia; Festa, Carmen; Fiorillo, Bianca; Di Leva, Francesco Saverio; Roselli, Rosalinda; Marchianò, Silvia; Biagioli, Michele; Spinelli, Lucio; Fiorucci, Stefano; Limongelli, Vittorio; Zampella, Angela; De Marino, Simona

doi:10.3390/molecules28062840

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Journal article

Expanding the library of 1,2,4-oxadiazole derivatives : Discovery of new farnesoid X receptor (FXR) antagonists/pregnane X receptor (PXR) agonists

Finamore, Claudia ORCID Department of Pharmacy, University of Naples “Federico II”, Naples, Italy
Festa, Carmen ORCID Department of Pharmacy, University of Naples “Federico II”, Naples, Italy
Fiorillo, Bianca ORCID Department of Pharmacy, University of Naples “Federico II”, Naples, Italy - Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, USA
Di Leva, Francesco Saverio ORCID Department of Pharmacy, University of Naples “Federico II”, Naples, Italy
Roselli, Rosalinda Department of Medicine and Surgery, University of Perugia, Perugia, Italy
Marchianò, Silvia ORCID Department of Medicine and Surgery, University of Perugia, Perugia, Italy
Biagioli, Michele ORCID Department of Medicine and Surgery, University of Perugia, Perugia, Italy
Spinelli, Lucio ORCID Department of Pharmacy, University of Naples “Federico II”, Naples, Italy
Fiorucci, Stefano ORCID Department of Medicine and Surgery, University of Perugia, Perugia, Italy
Limongelli, Vittorio ORCID Department of Pharmacy, University of Naples “Federico II”, Naples, Italy - Euler Institute (EUL), Università della Svizzera italiana, Switzerland
Zampella, Angela Department of Pharmacy, University of Naples “Federico II”, Naples, Italy
De Marino, Simona ORCID Department of Pharmacy, University of Naples “Federico II”, Naples, Italy

2023

Published in:

Molecules. - 2023, vol. 28, no. 6, p. 2840

Farnesoid X receptor antagonist

English Compounds featuring a 1,2,4-oxadiazole core have been recently identified as a new chemotype of farnesoid X receptor (FXR) antagonists. With the aim to expand this class of compounds and to understand the building blocks necessary to maintain the antagonistic activity, we describe herein the synthesis, the pharmacological evaluation, and the in vitro pharmacokinetic properties of a novel series of 1,2,4-oxadiazole derivatives decorated on the nitrogen of the piperidine ring with different N-alkyl and N-aryl side chains. In vitro pharmacological evaluation showed compounds 5 and 11 as the first examples of nonsteroidal dual FXR/Pregnane X receptor (PXR) modulators. In HepG2 cells, these compounds modulated PXR- and FXR-regulated genes, resulting in interesting leads in the treatment of inflammatory disorders. Moreover, molecular docking studies supported the experimental results, disclosing the ligand binding mode and allowing rationalization of the activities of compounds 5 and 11.

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