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.
Design, synthesis and biological evaluation of a class of bioisosteric oximes of the novel dual peroxisome proliferator-activated receptor α/γ ligand LT175 / L. Piemontese, G. Fracchiolla, A. Carrieri, M. Parente, A. Laghezza, G. Carbonara, S. Sblano, M. Tauro, F. Gilardi, P. Tortorella, A. Lavecchia, M. Crestani, B. Desvergne, F. Loiodice. - In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0223-5234. - 90(2015), pp. 583-594.
|Titolo:||Design, synthesis and biological evaluation of a class of bioisosteric oximes of the novel dual peroxisome proliferator-activated receptor α/γ ligand LT175|
|Parole Chiave:||Bioisosterism; Docking; Gene expression study; PPAR; Cell Line, Tumor; Dose-Response Relationship, Drug; Humans; Ligands; Molecular Docking Simulation; Molecular Structure; Oximes; PPAR alpha; PPAR gamma; Structure-Activity Relationship; Drug Design; Pharmacology; Drug Discovery; 3003; Pharmaceutical Science; Organic Chemistry|
|Settore Scientifico Disciplinare:||Settore BIO/10 - Biochimica|
Settore CHIM/08 - Chimica Farmaceutica
|Data di pubblicazione:||2015|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1016/j.ejmech.2014.11.044|
|Appare nelle tipologie:||01 - Articolo su periodico|