Structure–activity studies on 1,3-dioxane-2-carboxylic acid derivatives, a novel class of subtype-selective peroxisome proliferator-activated receptor α (PPARα) agonists

A series of 1,3-dioxane carboxylic acid derivatives was synthesized and evaluated for human PPAR transactivation activity. Structure–activity relationships on the phenyloxazole moiety of the lead compound 3 revealed that the introduction of small hydrophobic substituents at the 4-position of the terminal phenyl ring increased the PPARα agonist activity, and that the oxazole heterocycle was essential to the maintenance of both potency and PPARα subtype-selectivity. This investigation led to the identification of 14d (NS-220) and 14i as highly potent and selective human PPARα agonists. In KK-Ay type 2 diabetic mice, these compounds significantly lowered plasma triglyceride and very-low-density plus low-density lipoprotein cholesterol levels while simultaneously raising HDL cholesterol levels. Our results suggest that highly potent and subtype-selective PPARα agonists will be promising drugs for the treatment of metabolic disorders in type 2 diabetes.

The 1,3-dioxane-2-carboxylic acids 14d (NS-220) and 14i were identified as highly potent and selective human PPARα agonists. These compounds showed excellent hypolipidemic activity in type 2 diabetic KK-Ay mice.Figure optionsDownload as PowerPoint slide