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

  • ACS Med Chem Lett. 2018 Jul 31;9(9):935-940. doi: 10.1021/acsmedchemlett.8b00287.
Bharat Lagu  1 ,  Arthur F Kluge  1 ,  Effie Tozzo  1 ,  Ross Fredenburg  1 ,  Eric L Bell  1 ,  Matthew M Goddeeris  1 ,  Peter Dwyer  1 ,  Andrew Basinski  1 ,  Ramesh S Senaiar  2 ,  Mahaboobi Jaleel  2 ,  Nirbhay Kumar Tiwari  2 ,  Sunil K Panigrahi  2 ,  Narasimha Rao Krishnamurthy  2 ,  Taisuke Takahashi  3 ,  Michael A Patane  1
Affiliations
  • 1. Mitobridge, Inc. (a wholly owned subsidiary of Astellas Pharma.), 1030 Massachusetts Avenue, Cambridge, Massachusetts 02138, United States.
  • 2. Aurigene Discovery Technologies, Ltd., Bengaluru and Hyderabad, India.
  • 3. Astellas Pharma., Tsukuba, Japan.
PMID: 30258544 DOI: 10.1021/acsmedchemlett.8b00287
Abstract

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.

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