Identification of C-2 hydroxyethyl imidazopyrrolopyridines as potent JAK1 inhibitors with favorable physicochemical properties and high selectivity over JAK2.
J Med Chem
; 56(11): 4764-85, 2013 Jun 13.
Article
em En
| MEDLINE
| ID: mdl-23659214
ABSTRACT
Herein we report on the structure-based discovery of a C-2 hydroxyethyl moiety which provided consistently high levels of selectivity for JAK1 over JAK2 to the imidazopyrrolopyridine series of JAK1 inhibitors. X-ray structures of a C-2 hydroxyethyl analogue in complex with both JAK1 and JAK2 revealed differential ligand/protein interactions between the two isoforms and offered an explanation for the observed selectivity. Analysis of historical data from related molecules was used to develop a set of physicochemical compound design parameters to impart desirable properties such as acceptable membrane permeability, potent whole blood activity, and a high degree of metabolic stability. This work culminated in the identification of a highly JAK1 selective compound (31) exhibiting favorable oral bioavailability across a range of preclinical species and robust efficacy in a rat CIA model.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Piridinas
/
Pirróis
/
Antirreumáticos
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Janus Quinase 1
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Janus Quinase 2
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Compostos Heterocíclicos com 3 Anéis
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Imidazóis
Tipo de estudo:
Diagnostic_studies
/
Etiology_studies
/
Prognostic_studies
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article