Proline bis-amides as potent dual orexin receptor antagonists.
Bioorg Med Chem Lett
; 18(4): 1425-30, 2008 Feb 15.
Article
em En
| MEDLINE
| ID: mdl-18207395
ABSTRACT
A series of OX(2)R/OX(1)R dual orexin antagonists was prepared based on a proline bis-amide identified as a screening lead. Through a combination of classical and library synthesis, potency enhancing replacements for both amide portions were discovered. N-methylation of the benzimidazole moiety within the lead structure significantly reduced P-gp susceptibility while increasing potency, giving rise to good brain penetration. A compound from this series has demonstrated in vivo central activity when dosed peripherally in a pharmacodynamic model of orexin activity.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Prolina
/
Receptores de Neuropeptídeos
/
Receptores Acoplados a Proteínas G
/
Amidas
Limite:
Animals
Idioma:
En
Revista:
Bioorg Med Chem Lett
Assunto da revista:
BIOQUIMICA
/
QUIMICA
Ano de publicação:
2008
Tipo de documento:
Article
País de afiliação:
Estados Unidos