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

The X-ray structure of the previously reported PPARδ modulator <b>1</b> bound to the ligand binding domain (LBD) revealed that the amide moiety in <b>1</b> exists in the thermodynamically disfavored <i>cis</i>-amide orientation. Isosteric replacement of the <i>cis</i>-amide with five-membered heterocycles led to the identification of imidazole <b>17</b> (MA-0204), a potent, selective PPARδ modulator with good pharmacokinetic properties. MA-0204 was tested <i>in vivo</i> in mice and <i>in vitro</i> in patient-derived muscle myoblasts (from Duchenne Muscular Dystrophy (DMD) patients); <b>17</b> 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