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

ABSTRACT: The X-ray structure of the previously reported PPAR? 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 PPAR? 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 PPAR? target genes and improved fatty acid oxidation, which supports the therapeutic hypothesis for the study of MA-0204 in DMD patients.

SUBMITTER: Lagu B 

PROVIDER: S-EPMC6142063 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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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</  ...[more]

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