Identification of imidazo-pyrrolopyridines as novel and potent JAK1 inhibitors.
J Med Chem
; 55(12): 5901-21, 2012 Jun 28.
Article
em En
| MEDLINE
| ID: mdl-22591402
ABSTRACT
A therapeutic rationale is proposed for the treatment of inflammatory diseases, such as rheumatoid arthritis (RA), by specific targeting of the JAK1 pathway. Examination of the preferred binding conformation of clinically effective, pan-JAK inhibitor 1 led to identification of a novel, tricyclic hinge binding scaffold 3. Exploration of SAR through a series of cycloamino and cycloalkylamino analogues demonstrated this template to be highly tolerant of substitution, with a predisposition to moderate selectivity for the JAK1 isoform over JAK2. This study culminated in the identification of subnanomolar JAK1 inhibitors such as 22 and 49, having excellent cell potency, good rat pharmacokinetic characteristics, and excellent kinase selectivity. Determination of the binding modes of the series in JAK1 and JAK2 by X-ray crystallography supported the design of analogues to enhance affinity and selectivity.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Piridinas
/
Inibidores de Proteínas Quinases
/
Janus Quinase 1
/
Imidazóis
Tipo de estudo:
Diagnostic_studies
/
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
J Med Chem
Assunto da revista:
QUIMICA
Ano de publicação:
2012
Tipo de documento:
Article
País de afiliação:
Reino Unido