Effect of structurally constrained oxime–ether linker on PPAR subtype selectivity: Discovery of a novel and potent series of PPAR-pan agonists

A novel series of thaizole and oxazole containing phenoxy acetic acid derivatives is reported as PPAR-pan agonists. Incorporation of structurally constrained oxime–ether based linker in the chemotype of a potent PPARδ selective agonist GW-501516 was adapted as designing strategy. In vitro, selected test compounds 12a, 12c, 17a and 18a showed PPAR-pan agonists activities and among these four compounds tested, 12a emerged as highly potent and efficacious compound, while 17a exhibited moderate and balanced PPAR-pan agonistic activity. In vivo, selected test compounds 12a and 17a exhibited significant anti-hyperglycemic and anti-hyperlipidemic activities in relevant animal models. These results support our hypothesis that the introduction of structurally constrained oxime–ether linker between lipophilic tail and acidic head plays an important role in modulating subtype selectivity and subsequently led to the discovery of potent PPAR-pan agonists.

Effect of incorporation of structurally constrained oxime–ether linker in the chemotype of a PPARδ agonist (GW-501516) towards the modulation of PPAR subtype selectivity was studied. Selected compounds 12a and 17a exhibited balanced PPAR-pan agonistic activity (in vitro) and showed excellent anti-hyperglycemic and anti-hyperlipidemic activities in relevant animal models.Figure optionsDownload as PowerPoint slide