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

摘要

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