1,7-Naphthyridine 1-oxides as novel potent and selective inhibitors of p38 mitogen activated protein kinase.
J Med Chem
; 54(22): 7899-910, 2011 Nov 24.
Article
en En
| MEDLINE
| ID: mdl-21999461
ABSTRACT
The design, synthesis, and ability to inhibit p38α MAP kinase by a novel series of naphthyridine N-oxides will be described. Some of these compounds showed a significant reduction in the LPS-induced TNFα production in human whole blood. Structure-activity relationship studies revealed that N-oxide oxygen was essential for activity and was probably a determinant factor for its marked selectivity against other related kinases. After an extensive SAR exercise, several compounds from this series were identified as very potent p38α inhibitors. In vivo efficacy of some derivatives was demonstrated to reduce TNFα levels in an acute murine model of inflammation (ED(50) = 0.5 mg/kg in LPS-induced TNFα production when dosed orally 1.5 h prior to LPS administration). The oral efficacy was further demonstrated in a chronic model of adjuvant arthritis in rats with established disease when administered orally (ED(50) < 1 mg/kg).
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Antiinflamatorios no Esteroideos
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Proteínas Quinasas p38 Activadas por Mitógenos
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Naftiridinas
Tipo de estudio:
Etiology_studies
/
Prognostic_studies
Límite:
Animals
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Humans
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Male
Idioma:
En
Año:
2011
Tipo del documento:
Article