Identification of peroxisome proliferator-activated receptor ligands from a biased chemical library.
Chem Biol
; 4(12): 909-18, 1997 Dec.
Article
en En
| MEDLINE
| ID: mdl-9427656
ABSTRACT
BACKGROUND:
The peroxisome proliferator-activated receptors (PPARs) were cloned as orphan members of the nuclear receptor superfamily of transcription factors. The identification of subtype-selective ligands for PPARalpha and PPARgamma has led to the discovery of their roles in the regulation of lipid metabolism and glucose homeostasis. No subtype-selective PPARdelta ligands are available and the function of this subtype is currently unknown.RESULTS:
A three-component library was designed in which one of the monomers was biased towards the PPARs and the other two monomers were chosen to add chemical diversity. Synthesis and screening of the library resulted in the identification of pools with activity on each of the PPAR subtypes. Deconvolution of the pools with the highest activity on PPARdelta led to the identification of GW 2433 as the first high-affinity PPARdelta ligand. [3H]GW 2433 is an effective radioligand for use in PPARdelta competition-binding assays.CONCLUSIONS:
The synthesis of biased chemical libraries is an efficient approach to the identification of lead molecules for members of sequence-related receptor families. This approach is well suited to the discovery of small-molecule ligands for orphan receptors.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Compuestos de Fenilurea
/
Factores de Transcripción
/
Butiratos
/
Proteínas Nucleares
/
Receptores Citoplasmáticos y Nucleares
Tipo de estudio:
Diagnostic_studies
/
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Chem Biol
Asunto de la revista:
BIOLOGIA
/
BIOQUIMICA
/
QUIMICA
Año:
1997
Tipo del documento:
Article
País de afiliación:
Estados Unidos