Selective PPARδ Modulators Improve Mitochondrial Function: Potential Treatment for Duchenne Muscular Dystrophy (DMD).

The X-ray structure of the previously reported PPARδ modulator bound to the ligand binding domain (LBD) revealed that the amide moiety in exists in the thermodynamically disfavored -amide orientation. Isosteric replacement of the -amide with five-membered heterocycles led to the identification of imidazole (MA-0204), a potent, selective PPARδ modulator with good pharmacokinetic properties. MA-0204 was tested in mice and in patient-derived muscle myoblasts (from Duchenne Muscular Dystrophy (DMD) patients); altered the expression of PPARδ target genes and improved fatty acid oxidation, which supports the therapeutic hypothesis for the study of MA-0204 in DMD patients.