Identification of highly efficacious glucocorticoid receptor agonists with a potential for reduced clinical bone side effects.
J Med Chem
; 57(4): 1583-98, 2014 Feb 27.
Article
en En
| MEDLINE
| ID: mdl-24506830
ABSTRACT
Synthesis and structure-activity relationship (SAR) of a series of nonsteroidal glucocorticoid receptor (GR) agonists are described. These compounds contain "diazaindole" moieties and display different transcriptional regulatory profiles in vitro and are considered "dissociated" between gene transrepression and transactivation. The lead optimization effort described in this article focused in particular on limiting the transactivation of genes which result in bone side effects and these were assessed in vitro in MG-63 osteosarcoma cells, leading to the identification of (R)-18 and (R)-21. These compounds maintained anti-inflammatory activity in vivo in collagen induced arthritis studies in mouse but had reduced effects on bone relevant parameters compared to the widely used synthetic glucocorticoid prednisolone 2 in vivo. To our knowledge, we are the first to report on selective glucocorticoid ligands with reduced bone loss in a preclinical in vivo model.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Huesos
/
Receptores de Glucocorticoides
Tipo de estudio:
Diagnostic_studies
Límite:
Animals
/
Female
/
Humans
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2014
Tipo del documento:
Article
País de afiliación:
Estados Unidos