Selective and potent morpholinone inhibitors of the MDM2-p53 protein-protein interaction.
J Med Chem
; 57(6): 2472-88, 2014 Mar 27.
Article
en En
| MEDLINE
| ID: mdl-24548297
ABSTRACT
We previously reported the discovery of AMG 232, a highly potent and selective piperidinone inhibitor of the MDM2-p53 interaction. Our continued search for potent and diverse analogues led to the discovery of novel morpholinone MDM2 inhibitors. This change to a morpholinone core has a significant impact on both potency and metabolic stability compared to the piperidinone series. Within this morpholinone series, AM-8735 emerged as an inhibitor with remarkable biochemical potency (HTRF IC50 = 0.4 nM) and cellular potency (SJSA-1 EdU IC50 = 25 nM), as well as pharmacokinetic properties. Compound 4 also shows excellent antitumor activity in the SJSA-1 osteosarcoma xenograft model with an ED50 of 41 mg/kg. Lead optimization toward the discovery of this inhibitor as well as key differences between the morpholinone and the piperidinone series will be described herein.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Morfolinas
/
Proteína p53 Supresora de Tumor
/
Proteínas Proto-Oncogénicas c-mdm2
/
Acetatos
/
Antineoplásicos
Límite:
Animals
/
Humans
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2014
Tipo del documento:
Article
País de afiliación:
Estados Unidos