Expanding the library of 1,2,4-oxadiazole derivatives
Discovery of new farnesoid X receptor (FXR) antagonists/pregnane X receptor (PXR) agonists
Informazioni aggiuntive
Autori
Finamore C.,
Festa C.,
Fiorillo B.,
Di Leva F. S.,
Roselli R.,
Marchianò S.,
Biagioli M.,
Spinelli L.,
Fiorucci S.,
Limongelli V.,
Zampella A.,
De Marino S.
Tipo
Articolo pubblicato in rivista scientifica
Anno
2023
Lingua
Inglese
Sommario
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.
Parole chiave
Farnesoid X receptor antagonist, Pregnane X receptor agonist, 1,2,4-oxadiazole, Inflammatory disorders
Periodico
Molecules
Volume
28
Numero ( Mese )
6
Pagine (o numero dell’articolo)
2840
Diffusione
Licenza
CC BY
Visibilità
Pubblico
Status open access
Gold
