2. Academic Validation
  3. Selective PPARδ Modulators Improve Mitochondrial Function: Potential Treatment for Duchenne Muscular Dystrophy (DMD)

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

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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