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
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.
- Collections
- Language
-
- English
- Classification
- Pharmacology, therapeutics, toxicology
- License
- CC BY
- Open access status
- gold
- Identifiers
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- DOI 10.3390/molecules28062840
- ARK ark:/12658/srd1328293
- Persistent URL
- https://n2t.net/ark:/12658/srd1328293
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