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Design and Structural Analysis of Novel Pharmacophores for Potent and Selective Peroxisome Proliferator-activated Receptor γ Agonists
- Source :
- Journal of Medicinal Chemistry. 52:2618-2622
- Publication Year :
- 2009
- Publisher :
- American Chemical Society (ACS), 2009.
-
Abstract
- Utilizing medicinal chemistry design strategies such as benzo splitting and ring expansion, we converted PPARalpha/gamma dual agonist 1 to selective PPARgamma agonists 19 and 20. Compounds 19 and 20 were 2- to 4-fold better than rosiglitazone at PPARgamma receptor, with 80- to 100-fold PPARgamma selectivity over PPARalpha receptor. X-ray cocrystal studies in PPARgamma and modeling studies in PPARalpha give molecular insights for the improved PPARgamma potency and selectivity for 19 when compared to 1.
- Subjects :
- Models, Molecular
Agonist
Molecular model
Stereochemistry
medicine.drug_class
Hydroxybutyrates
Peroxisome proliferator-activated receptor
Crystallography, X-Ray
Rosiglitazone
Structure-Activity Relationship
Drug Discovery
medicine
Hypoglycemic Agents
Protein Isoforms
Structure–activity relationship
PPAR alpha
Receptor
chemistry.chemical_classification
PPAR gamma
chemistry
Nuclear receptor
Quinolines
Molecular Medicine
Thiazolidinediones
Pharmacophore
medicine.drug
Subjects
Details
- ISSN :
- 15204804 and 00222623
- Volume :
- 52
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....f87ee1cb34adea064694e99af8e12e2c