Structure-activity studies on 1,3-dioxane-2-carboxylic acid derivatives, a novel class of subtype-selective peroxisome proliferator-activated receptor alpha (PPARalpha) agonists.
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Asaki T, Aoki T, Hamamoto T, Sugiyama Y, Ohmachi S, Kuwabara K, Murakami K, Todo M
Structure-activity studies on 1,3-dioxane-2-carboxylic acid derivatives, a novel class of subtype-selective peroxisome proliferator-activated receptor alpha (PPARalpha) agonists.
Bioorg Med Chem. 2008 Jan 15;16(2):981-94. Epub 2007 Oct 9.
- PubMed ID
- 17964792 [ View in PubMed]
- Abstract
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.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Bezafibrate Peroxisome proliferator-activated receptor alpha EC 50 (nM) 30000 N/A N/A Details Bezafibrate Peroxisome proliferator-activated receptor delta EC 50 (nM) 30000 N/A N/A Details Bezafibrate Peroxisome proliferator-activated receptor gamma EC 50 (nM) 3000 N/A N/A Details