Substituted 2-[(4-aminomethyl)phenoxy]-2-methylpropionic acid PPARalpha agonists. 1. Discovery of a novel series of potent HDLc raising agents.
J Med Chem
; 50(4): 685-95, 2007 Feb 22.
Article
en En
| MEDLINE
| ID: mdl-17243659
ABSTRACT
The peroxisome proliferator activated receptors PPARalpha, PPARgamma, and PPARdelta are ligand-activated transcription factors that play a key role in lipid homeostasis. The fibrates raise circulating levels of high-density lipoprotein cholesterol and lower levels of triglycerides in part through their activity as PPARalpha agonists; however, the low potency and restricted selectivity of the fibrates may limit their efficacy, and it would be desirable to develop more potent and selective PPARalpha agonists. Modification of the selective PPARdelta agonist 1 (GW501516) so as to incorporate the 2-aryl-2-methylpropionic acid group of the fibrates led to a marked shift in potency and selectivity toward PPARalpha agonism. Optimization of the series gave 25a, which shows EC50 = 4 nM on PPARalpha and at least 500-fold selectivity versus PPARdelta and PPARgamma. Compound 25a (GW590735) has been progressed to clinical trials for the treatment of diseases of lipid imbalance.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Propionatos
/
Tiazoles
/
PPAR alfa
/
HDL-Colesterol
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2007
Tipo del documento:
Article
País de afiliación:
Estados Unidos