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

作者：Fresno N; Macias Gonzalez M; Torres Zaguirre A; Romero Cuevas M; Sanz Camacho P; Elguero T J; Pavon F J; Rodriguez de Fonseca F; Goya P; Perez Fernandez R

来源：Journal of Medicinal Chemistry, 2015, 58(16): 6639-6652.

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 PPAR alpha 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 PPAR alpha receptor, thus validating the oxazolidinone template for PPAR activity. In addition, two compounds, 2 and 4, showed dual PPAR alpha/PPAR gamma agonism and interesting food intake reduction in rats.

• 出版日期2015-8-27