Expanding the library of 1,2,4-oxadiazole derivatives
Discovery of new farnesoid X receptor (FXR) antagonists/pregnane X receptor (PXR) agonists
Additional information
Authors
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.
Type
Journal Article
Year
2023
Language
English
Abstract
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.
Keywords
Farnesoid X receptor antagonist, Pregnane X receptor agonist, 1,2,4-oxadiazole, Inflammatory disorders
Journal
Molecules
Volume
28
Number ( Month )
6
Pages (or article number)
2840
Diffusion
License
CC BY
Visibility
Public
Status open access
Gold
