Second generation 2-pyridyl biphenyl amide inhibitors of the hedgehog pathway.
Bioorg Med Chem Lett
; 20(22): 6748-53, 2010 Nov 15.
Article
en En
| MEDLINE
| ID: mdl-20875741
ABSTRACT
Potent and efficacious inhibitors of the hedgehog pathway for the treatment of cancer have been prepared using the 2-pyridyl biphenyl amide scaffold common to the clinical lead GDC-0449. Analogs with polar groups in the para-position of the aryl amide ring optimized potency, had minimal CYP inhibition, and possessed good exposure in rats. Compounds 9d and 14f potently inhibited hedgehog signaling as measured by Gli1 mRNA and were found to be equivalent or more potent than GDC-0449, respectively, when studied in a Ptch(+/-) medulloblastoma allograft model, that is, highly dependent on hedgehog signaling.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Piridinas
/
Proteínas Hedgehog
/
Amidas
Límite:
Animals
Idioma:
En
Revista:
Bioorg Med Chem Lett
Asunto de la revista:
BIOQUIMICA
/
QUIMICA
Año:
2010
Tipo del documento:
Article
País de afiliación:
Estados Unidos