3区 · 医学
Article
作者: Goddeeris, Matthew M. ; Krishnamurthy, Narasimha Rao ; Bell, Eric L. ; Dwyer, Peter ; Takahashi, Taisuke ; Lagu, Bharat ; Kluge, Arthur F. ; Tiwari, Nirbhay Kumar ; Panigrahi, Sunil K. ; Jaleel, Mahaboobi ; Patane, Michael A. ; Basinski, Andrew ; Fredenburg, Ross ; Senaiar, Ramesh S. ; Tozzo, Effie
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.