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

Area of Science:

• Medicinal Chemistry
• Molecular Pharmacology
• Biochemistry

Background:

• The PPARδ modulator 1 exhibited a cis-amide orientation in its ligand binding domain (LBD).
• This cis-amide conformation is thermodynamically disfavored, suggesting potential for structural optimization.

Purpose of the Study:

• To identify novel PPARδ modulators with improved properties.
• To explore the therapeutic potential of PPARδ modulation in Duchenne Muscular Dystrophy (DMD).

Main Methods:

• Isosteric replacement of the cis-amide moiety in compound 1 with five-membered heterocycles.
• Structural analysis and characterization of the resulting compounds.
• In vivo testing in mice and in vitro testing in patient-derived muscle myoblasts.

Main Results:

• Identification of imidazole 17 (MA-0204) as a potent and selective PPARδ modulator.
• MA-0204 demonstrated good pharmacokinetic properties.
• MA-0204 altered PPARδ target gene expression and enhanced fatty acid oxidation in DMD myoblasts.

Conclusions:

• The imidazole derivative MA-0204 represents a promising therapeutic candidate for DMD.
• PPARδ modulation may offer a viable strategy for treating DMD by improving muscle metabolism.