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

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 identifica...

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Published in:ACS medicinal chemistry letters 2018-09, Vol.9 (9), p.935-940
Main Authors: Lagu, Bharat, Kluge, Arthur F, Tozzo, Effie, Fredenburg, Ross, Bell, Eric L, Goddeeris, Matthew M, Dwyer, Peter, Basinski, Andrew, Senaiar, Ramesh S, Jaleel, Mahaboobi, Tiwari, Nirbhay Kumar, Panigrahi, Sunil K, Krishnamurthy, Narasimha Rao, Takahashi, Taisuke, Patane, Michael A
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Language:English
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Summary: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.
ISSN:1948-5875
1948-5875
DOI:10.1021/acsmedchemlett.8b00287