Design, synthesis and biological evaluation of a class of bioisosteric oximes of the novel dual peroxisome proliferator-activated receptor α/γ ligand LT175.

Détails

ID Serval
serval:BIB_DBC58EF8C795
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Design, synthesis and biological evaluation of a class of bioisosteric oximes of the novel dual peroxisome proliferator-activated receptor α/γ ligand LT175.
Périodique
European Journal of Medicinal Chemistry
Auteur(s)
Piemontese L., Fracchiolla G., Carrieri A., Parente M., Laghezza A., Carbonara G., Sblano S., Tauro M., Gilardi F., Tortorella P., Lavecchia A., Crestani M., Desvergne B., Loiodice F.
ISSN
1768-3254 (Electronic)
ISSN-L
0223-5234
Statut éditorial
Publié
Date de publication
2015
Peer-reviewed
Oui
Volume
90
Pages
583-594
Langue
anglais
Résumé
The effects resulting from the introduction of an oxime group in place of the distal aromatic ring of the diphenyl moiety of LT175, previously reported as a PPARα/γ dual agonist, have been investigated. This modification allowed the identification of new bioisosteric ligands with fairly good activity on PPARα and fine-tuned moderate activity on PPARγ. For the most interesting compound (S)-3, docking studies in PPARα and PPARγ provided a molecular explanation for its different behavior as full and partial agonist of the two receptor isotypes, respectively. A further investigation of this compound was carried out performing gene expression studies on HepaRG cells. The results obtained allowed to hypothesize a possible mechanism through which this ligand could be useful in the treatment of metabolic disorders. The higher induction of the expression of some genes, compared to selective agonists, seems to confirm the importance of a dual PPARα/γ activity which probably involves a synergistic effect on both receptor subtypes.
Mots-clé
PPAR, Bioisosterism, Docking, Gene expression study
Pubmed
Web of science
Création de la notice
15/02/2015 22:33
Dernière modification de la notice
18/02/2020 7:20
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