Synthesis and biological and structural characterization of the dual-acting peroxisome proliferator-activated receptor alpha/gamma agonist ragaglitazar.
J Med Chem
; 46(8): 1306-17, 2003 Apr 10.
Article
em En
| MEDLINE
| ID: mdl-12672231
ABSTRACT
A new and improved synthesis of the peroxisome proliferator-activated receptor (PPAR) agonist ragaglitazar applicable for large-scale preparation has been developed. The convergent synthetic procedure was based on a novel enzymatic kinetic resolution step. The conformation of ragaglitazar bound to the hPPARgamma receptor was quite different compared to the single-crystal structures of the l-arginine salt of ragaglitazar. In particular, the phenoxazine ring system had varying orientations. Ragaglitazar had high affinity for the hPPARalpha and -gamma receptors with IC(50) values of 0.98 and 0.092 microM, respectively. The lack of hPPARdelta activity could be explained by the absence of binding in the tail-up pocket in the hPPARdelta receptor, in contrast to the hPPARdelta agonist GW2433, which was able to bind in both the tail-up and tail-down pockets of the receptor.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Oxazinas
/
Fenilpropionatos
/
Fatores de Transcrição
/
Receptores Citoplasmáticos e Nucleares
/
Hipoglicemiantes
Tipo de estudo:
Prognostic_studies
Idioma:
En
Revista:
J Med Chem
Ano de publicação:
2003
Tipo de documento:
Article