Expanding the library of 1,2,4-oxadiazole derivatives : Discovery of new farnesoid X receptor (FXR) antagonists/pregnane X receptor (PXR) agonists
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Finamore, Claudia
ORCID
Department of Pharmacy, University of Naples “Federico II”, Naples, Italy
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Festa, Carmen
ORCID
Department of Pharmacy, University of Naples “Federico II”, Naples, Italy
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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
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Di Leva, Francesco Saverio
ORCID
Department of Pharmacy, University of Naples “Federico II”, Naples, Italy
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Roselli, Rosalinda
Department of Medicine and Surgery, University of Perugia, Perugia, Italy
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Marchianò, Silvia
ORCID
Department of Medicine and Surgery, University of Perugia, Perugia, Italy
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Biagioli, Michele
ORCID
Department of Medicine and Surgery, University of Perugia, Perugia, Italy
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Spinelli, Lucio
ORCID
Department of Pharmacy, University of Naples “Federico II”, Naples, Italy
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Fiorucci, Stefano
ORCID
Department of Medicine and Surgery, University of Perugia, Perugia, Italy
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Limongelli, Vittorio
ORCID
Department of Pharmacy, University of Naples “Federico II”, Naples, Italy - Euler Institute (EUL), Università della Svizzera italiana, Switzerland
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Zampella, Angela
Department of Pharmacy, University of Naples “Federico II”, Naples, Italy
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De Marino, Simona
ORCID
Department of Pharmacy, University of Naples “Federico II”, Naples, Italy
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Published in:
- Molecules. - 2023, vol. 28, no. 6, p. 2840
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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Language
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Classification
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Pharmacology, therapeutics, toxicology
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License
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CC BY
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Open access status
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gold
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Persistent URL
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https://n2t.net/ark:/12658/srd1328293
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