Design, synthesis, and evaluation of a new class of noncyclic 1,3-dicarbonyl compounds as PPARα selective activators

Lipid accumulation in nonadipose tissues is increasingly linked to the development of type 2 diabetes in obese individuals. We report here the design, synthesis, and evaluation of a series of novel PPARα selective activators containing 1,3-dicarbonyl moieties. Structure–activity relationship studies led to the identification of PPARα selective activators (compounds 10, 14, 17, 18, and 21) with stronger potency and efficacy to activate PPARα over PPARγ and PPARδ. Experiments in vivo showed that compounds 10, 14, and 17 had blood glucose lowering effect in diabetic db/db mouse model after two weeks oral dosing. The data strongly support further testing of these lead compounds in other relevant disease animal models to evaluate their potential therapeutic benefits.