Rapid development of piperidine carboxamides as potent and selective anaplastic lymphoma kinase inhibitors.
J Med Chem
; 55(4): 1698-705, 2012 Feb 23.
Article
em En
| MEDLINE
| ID: mdl-22263917
ABSTRACT
Piperidine carboxamide 1 was identified as a novel inhibitor of anaplastic lymphoma kinase (ALK enzyme assay IC(50) = 0.174 µM) during high throughput screening, with selectivity over the related kinase insulin-like growth factor-1 (IGF1R). The X-ray cocrystal structure of 1 with the ALK kinase domain revealed an unusual DFG-shifted conformation, allowing access to an extended hydrophobic pocket. Structure-activity relationship (SAR) studies were focused on the rapid parallel optimization of both the right- and left-hand side of the molecule, culminating in molecules with improved potency and selectivity over IGF1R.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Piperidinas
/
Pirimidinas
/
Receptores Proteína Tirosina Quinases
/
Amidas
/
Antineoplásicos
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article