Modulation of PPAR receptor subtype selectivity of the ligands: Aliphatic chain vs aromatic ring as a spacer between pharmacophore and the lipophilic moiety

Oxazole containing glycine and oximinobutyric acid derivatives were synthesized as PPARα agonists by incorporating polymethylene spacer as a replacement of commonly used phenylene group that connects the acidic head with lipophilic tail. Compound 13a was found to be a selective and potent PPARα agonist. Further 1,3-dioxane-2-carboxylic acid derivative 20 was synthesized by replacing the tetramethylene spacer of NS-220, a selective PPARα agonist with phenylene group and found to exhibit PPARα/γ dual agonism. These results suggest that compounds possessing polymethylene spacer between pharmacophore and lipophilic tail exhibit predominantly PPARα agonism whereas those with an aromatic phenylene spacer shows PPARα/γ dual agonism.

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