PT  - JOURNAL ARTICLE
AU  - Kenji Kuwabara
AU  - Kohji Murakami
AU  - Makoto Todo
AU  - Tomiyoshi Aoki
AU  - Tetsuo Asaki
AU  - Masatoshi Murai
AU  - Junichi Yano
TI  - A Novel Selective Peroxisome Proliferator-Activated Receptor α 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 Lipoprotein Profiles in KK-A<sup>y</sup> Mice
AID  - 10.1124/jpet.103.064659
DP  - 2004 Jun 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 970--977
VI  - 309
IP  - 3
4099  - http://jpet.aspetjournals.org/content/309/3/970.short
4100  - http://jpet.aspetjournals.org/content/309/3/970.full
SO  - J Pharmacol Exp Ther2004 Jun 01; 309
AB  - 2-Methyl-c-5-[4-[5-methyl-2-(4-methylphenyl)-4-oxazolyl]butyl]-1,3-dioxane-r-2-carboxylic acid (NS-220) was newly synthesized and demonstrated to be a novel potent peroxisome proliferator-activated receptor α (PPARα) agonist with high subtype selectivity. In cell-based reporter gene assays, the EC50 values of NS-220 for human PPARα, PPARγ, and PPARδ were 1.9 × 10-8, 9.6 × 10-6, and >10-4 M, respectively, and for mouse PPARα, PPARγ, and PPARδ were 5.5 × 10-8, 3.3 × 10-5, and >10-4 M, respectively. In addition, [3H]NS-220 bound to the ligand-binding domain of human PPARα with a KD value of 1.85 × 10-7 M. Fenofibric acid and bezafibrate showed weak agonist activity for PPARα (EC50, 2–8 × 10-5 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 abolished in PPARα-deficient mice. In KK-Ay mice, an animal model of type-2 diabetes, NS-220 (0.3–1 mg/kg p.o.; 4 days) and fenofibrate (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 triglyceride-rich lipoprotein levels. In conclusion, a newly synthesized dioxanecarboxylic acid derivative, NS-220, is a potent and highly selective PPARα 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. The American Society for Pharmacology and Experimental Therapeutics