Design, synthesis and biological evaluation of a class of bioisosteric oximes of the novel dual peroxisome proliferator-activated receptor α/γ ligand LT175
| Autor: | Antonio Lavecchia, Antonio Carrieri, Sabina Sblano, Marilena Tauro, Béatrice Desvergne, Giuseppe Fracchiolla, Fulvio Loiodice, Mariagiovanna Parente, Luca Piemontese, Antonio Laghezza, Maurizio Crestani, Paolo Tortorella, Giuseppe Carbonara, Federica Gilardi |
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| Přispěvatelé: | Piemontese, L, Fracchiolla, G, Carrieri, A, Parente, M, Laghezza, A, Carbonara, G, Sblano, S, Tauro, M, Gilardi, F, Tortorella, P, Lavecchia, Antonio, Crestani, M, Desvergne, B, Loiodice, F. |
| Rok vydání: | 2015 |
| Předmět: |
Agonist
Stereochemistry medicine.drug_class Peroxisome proliferator-activated receptor Ligands Partial agonist Docking Structure-Activity Relationship chemistry.chemical_compound Cell Line Tumor Oximes Drug Discovery Gene expression medicine Humans PPAR alpha Receptor Bioisosterism Pharmacology chemistry.chemical_classification Dose-Response Relationship Drug Molecular Structure Ligand Organic Chemistry General Medicine Oxime Molecular Docking Simulation PPAR gamma chemistry Biochemistry Docking (molecular) Drug Design peroxisome proliferator-activated receptors (PPARs) |
| Zdroj: | European Journal of Medicinal Chemistry. 90:583-594 |
| ISSN: | 0223-5234 |
| DOI: | 10.1016/j.ejmech.2014.11.044 |
| Popis: | 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 PPARalpha/gamma dual agonist, have been investigated. This modification allowed the identification of new bioisosteric ligands with fairly good activity on PPARalpha and fine-tuned moderate activity on PPARgamma. For the most interesting compound (S)-3, docking studies in PPARalpha and PPARalpha 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 PPARalpha/gamma activity which probably involves a synergistic effect on both receptor subtypes. |
| Databáze: | OpenAIRE |
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