Abstract
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.
Footnotes
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DOI: 10.1124/jpet.103.064659.
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ABBREVIATIONS: PPAR, peroxisome proliferator-activated receptor; HDL, high-density lipoprotein; hPPARαLBD, human PPARα ligand-binding domain; VLDL, very-low-density lipoprotein; GW9578, 2-[4-{2-[3-(2,4-difluorophenyl)-1-heptylureido]ethyl}phenylsulfanyl]-2-methylpropanoic acid; GW7647, 2-[4-{2-[3-cyclohexyl-1-(4-cyclohexylbutyl)ureido]ethyl}phenylsulfanyl]-2-methylpropanoic acid; KCL1998001079, 2-[4-methoxy-3-({[4-(trifluoromethyl)benzyl]amino}carbonyl)benzyl]butanoic acid; LY518674, 2-methyl-2-(4-{3-[1-(4-methylbenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl]propyl}phenoxy)propanoic acid; Wy-14643, ({4-chloro-6-[(2,3-dimethylphenyl)amino]pyrimidin-2-yl}thio)acetic acid.
- Received December 21, 2003.
- Accepted February 24, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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