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

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.