Synthesis and dual PPARα/δ agonist effects of 1,4-disubstituted 1,2,3-triazole analogues of GW 501516

Ten 1,4-disubstituted 1,2,3-triazoles 2a–2j were prepared and tested for their ability to increase oleic acid oxidation in human myotubes using a high-throughput multiwell assay. Compounds 2e (2-{4-[(1-(3-fluoro-4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)methylthio]-2-methylphenoxy}acetic acid) and 2i (2-{4-[(1-(3-chloro-4-(trifluoromethoxy)phenyl)-1H-1,2,3-triazol-4-yl)methylthio]-2-methylphenoxy}acetic acid) exhibited potent agonist activities. Compounds 2e and 2i also exhibited powerful agonist effects for both PPARα and PPARδ in a luciferase-based assay. Consequently, these triazoles can be categorized as dual PPAR agonists.

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