ABSTRACT
A new series of 1,3-dioxane-2-carboxylic acid derivatives was synthesized and evaluated for agonist activity at human peroxisome proliferator-activated receptor (PPAR) subtypes. Structure-activity relationship studies led to the identification of 2-methyl-c-5-[4-(5-methyl-2-phenyl-1,3-oxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylic acid 4b as a potent PPARalpha agonist with high subtype selectivity at human receptor subtypes. This compound exhibited a substantial hypolipidemic effect in type 2 diabetic KK-A(y) mice.
Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Dioxanes/chemical synthesis , Dioxanes/pharmacology , Oxazoles/chemical synthesis , Oxazoles/pharmacology , PPAR alpha/agonists , Animals , Blood Glucose/metabolism , Disease Models, Animal , Humans , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/pharmacology , Hypolipidemic Agents/chemical synthesis , Hypolipidemic Agents/pharmacology , Lipoproteins/blood , Magnetic Resonance Spectroscopy , Mice , Mice, Inbred Strains , Molecular Structure , Structure-Activity Relationship , Triglycerides/bloodABSTRACT
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 PPARalpha agonist activity, and that the oxazole heterocycle was essential to the maintenance of both potency and PPARalpha subtype-selectivity. This investigation led to the identification of 14d (NS-220) and 14i as highly potent and selective human PPARalpha agonists. In KK-A(y) 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 PPARalpha agonists will be promising drugs for the treatment of metabolic disorders in type 2 diabetes.