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CARDIOVASCULAR

A Novel Selective Peroxisome Proliferator-Activated Receptor 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^y Mice

Discovery Research Laboratories, Nippon Shinyaku Co., Ltd., Kyoto, Japan

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 (PPAR) agonist with high subtype selectivity. In cell-based reporter gene assays, the EC₅₀ values of NS-220 for human PPAR, PPAR, and PPAR were 1.9 x 10^-8, 9.6 x 10^-6, and >10^-4 M, respectively, and for mouse PPAR, PPAR, and PPAR were 5.5 x 10^-8, 3.3 x 10^-5, and >10^-4 M, respectively. In addition, [³H]NS-220 bound to the ligand-binding domain of human PPAR with a K_D value of 1.85 x 10^-7 M. Fenofibric acid and bezafibrate showed weak agonist activity for PPAR (EC₅₀, 2–8 x 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 PPAR-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 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 PPAR 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.

Address correspondence to: Dr. Kenji Kuwabara, Discovery Research Laboratories, Nippon Shinyaku Co., Ltd., 14 Nishinosho-Monguchi-Cho, Kisshoin, Minami-Ku, Kyoto 601-8550, Japan. E-mail: k.kuwabara{at}po.nippon-shinyaku.co.jp

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