Novel Oxazolidinone-Based Peroxisome Proliferator Activated Receptor Agonists: Molecular Modeling, Synthesis, and Biological Evaluation

• Published in: Journal of medicinal chemistry 2015-08, Vol.58 (16), p.6639-6652
• Main Authors: Fresno, N, Macías-González, M, Torres-Zaguirre, A, Romero-Cuevas, M, Sanz-Camacho, P, Elguero, J, Pavón, F. J, Rodríguez de Fonseca, F, Goya, P, Pérez-Fernández, R
• Format: Article
• Language: English
• Subjects: Animals; Appetite Depressants - chemical synthesis; Appetite Depressants - pharmacology; Dose-Response Relationship, Drug; Eating - drug effects; Ligands; Models, Molecular; Molecular Conformation; Oxazoles - chemical synthesis; Oxazoles - pharmacology; PPAR alpha - agonists; PPAR gamma - agonists; Rats; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.5b00849

A series of new peroxisome proliferator activated receptors (PPARs) chiral ligands have been designed following the accepted three-module structure comprising a polar head, linker, and hydrophobic tail. The majority of the ligands incorporate the oxazolidinone moiety as a novel polar head, and the nature of the hydrophobic tail has also been varied. Docking studies using the crystal structure of an agonist bound to the ligand binding domain of the PPARα receptor have been performed as a tool for their design. Suitable synthetic procedures have been developed, and compounds with different stereochemistries have been prepared. Evaluation of basal and ligand-induced activity proved that several compounds showed agonist activity at the PPARα receptor, thus validating the oxazolidinone template for PPAR activity. In addition, two compounds, 2 and 4, showed dual PPARα/PPARγ agonism and interesting food intake reduction in rats.