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

Abstract

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.

Targeting Peroxisome Proliferator-Activated Receptor Delta (PPARδ): A Medicinal Chemistry Perspective

“…The in vivo study on gene expression data analysis indicated that compound 36 is safer than GW501516. 166 Lagu et al 109 also reported another potent and selective PPARδ agonist, MA-0204 (37) by isosteric replacement of the amide group with an imidazole ring. Furthermore, in vitro and in vivo assays in mice and rats indicated that compound 37 has a favorable pharmacokinetic profile, suggesting that the compound is a potential agent for the treatment of Duchenne muscular dystrophy (DMD).…”

“…A SAR study revealed the importance of the isosteric replacement of linker (amide group) with imidazole moiety, and replacing the 2-furyl group with 4-trifluoromethoxy group for improved PPARδ selectivity over PPARα and PPARγ. 109 Finally, on the basis of the structure of GW501516 and compound 35, we recently synthesized and detailed an SAR of Y-shaped biaryl analogues and identified the novel compound (38), with a high transactivation activity (PPARδ EC 50 = 2.6 nM) and over 3846-fold selectivity to PPARα and PPARγ. 121 Compound 38 was designed based on the structure of GW501516 by replacing a thiazole group with a phenyl ring (Figure 10B).…”

“…MA-0204 (compound 37 ), a potent and selective PPARδ agonist, increased the transcription of PPARδ target gene PDK4 in the muscles of mice. In DMD patient-derived muscle myoblasts, MA-0204 improved fatty acid oxidation and increased expression of PPARδ target genes PDK4, ANGPTL4, and CPT1a . ASP0367 (MA-0211, structure not disclosed) is currently under phase I clinical trial in pediatric male subjects with DMD ( identifier NCT04184882).…”

“…Lagu et al ,, from Mitobridge, a wholly owned subsidiary of Astellas Pharma, reported several compounds synthesized by the structural modification of benzamide PPARδ agonist 35 . The group identified compound 36 as a selective PPARδ agonist with improved pharmacokinetic properties using structure–activity relationships.…”

“…In Vitro Potency of Synthetic PPARδ Agonists (nM) on Human PPAR Receptor Lagu et al109,165,166 from Mitobridge, a wholly owned subsidiary of Astellas Pharma, reported several compounds synthesized by the structural modification of benzamide PPARδ agonist 35. The group…”