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Structure-activity studies on 1,3-dioxane-2-carboxylic acid derivatives, a novel class of subtype-selective peroxisome proliferator-activated receptor alpha (PPARalpha) agonists
- Source :
- Bioorganicmedicinal chemistry. 16(2)
- Publication Year :
- 2007
-
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.
- Subjects :
- Agonist
medicine.drug_class
Carboxylic acid
Clinical Biochemistry
Pharmaceutical Science
Peroxisome proliferator-activated receptor
Biochemistry
Dioxanes
chemistry.chemical_compound
Transactivation
Mice
Structure-Activity Relationship
Drug Discovery
medicine
Structure–activity relationship
Animals
Combinatorial Chemistry Techniques
Humans
PPAR alpha
Molecular Biology
Oxazoles
Oxazole
chemistry.chemical_classification
Molecular Structure
Cholesterol
Organic Chemistry
chemistry
Nuclear receptor
Molecular Medicine
lipids (amino acids, peptides, and proteins)
Subjects
Details
- ISSN :
- 14643391
- Volume :
- 16
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- Bioorganicmedicinal chemistry
- Accession number :
- edsair.doi.dedup.....f2866d3073594659655aca56a8f2dccf