A Novel Selective Peroxisome Proliferator-Activated Receptor alpha Agonist,2-Methyl-c-5-[4-[5-methyl-2-(4-methylphenyl)-4-oxazolyl]butyl]-1,3-dioxane-r-2-carboxylic acid (NS-220),Potently Decreases Plasma Triglyceride and Glucose Levels and Modifies

摘要

2-Methyl-c-5-[4-[5-methyl-2-(4-methylphenyl)-4-oxazolyl]bu-tyl]-1|,3-dioxane-r-2-carboxylic acid (NS-220) was newly synthesized and demonstrated to be a novel potent peroxisome proliferator-activated receptor a (PPARalpha) agonist with high subtype selectivity.In cell-based reporter gene assays,the EC_(50) values of NS-220 for human PPARalpha,PPARgamma,and PPARS were 1.910~(-8),9.6X10~(-6),and>10~(-4) M,respectively,and for mouse PPARalpha,PPARgamma,and PPARdelta were 5.5X10~(-8),3.3 X10~(-5),and>10~(-4) M,respectively.In addition,[~3H]NS-220 bound to the ligand-binding domain of human PPARalpha with a K_D value of 1.85X10~(-7) M.Fenofibric acid and bezafibrate showed weak agonist activity for PPARa (EC_(50),2-8X10~(-5) M),with poor subtype selectivity.NS-220 (0.1-3 mg/kg p.o.) decreased plasma triglyceride levels in ddY mice in a dose-dependent manner,but its hypolipidemic activity was abolishedin PPARalpha-deficient mice.In KK-A~y mice,an animal model of type-2 diabetes,NS-220 (0.3-1 mg/kg p.o.;4 days) and feno-fibrate (100-300 mg/kg p.o.;4 days) decreased plasma triglyceride and glucose levels in a dose-dependent manner.In a 2-week repeated administration test,NS-220 (0.3-1 mg/kg p.o.) decreased plasma glucose levels markedly without increasing in plasma insulin levels.Furthermore,NS-220 increased high-density lipoprotein levels and decreased triglyc-eride-rich lipoprotein levels.In conclusion,a newly synthesized dioxanecarboxylic acid derivative,NS-220,is a potent and highly selective PPARalpha agonist that ameliorates metabolic disorders in diabetic mice.These results strongly suggest that it will be a promising drug for the treatment of hyperlipidemia or metabolic disorders in type-2 diabetes.