RESUMO
The MAPK (mitogen-activated protein kinase) p38 is an important mediator of inflammation and of inflammatory and neuropathic pain. We have described recently that docking-groove-dependent interactions are important for p38 MAPK-mediated signal transduction. Thus virtual screening was performed to identify putative docking-groove-targeted p38 MAPK inhibitors. Several compounds of the benzo-oxadiazol family were identified with low micromolar inhibitory activity both in a p38 MAPK activity assay, and in THP-1 human monocytes acting as inhibitors of LPS (lipopolysaccharide)-induced TNFα (tumour necrosis factor α) secretion. Positions 2 and 5 in the phenyl ring are essential for the described inhibitory activity with a chloride in position 5 and a methyl group in position 2 yielding the best results, giving an IC50 value of 1.8 µM (FGA-19 compound). Notably, FGA-19 exerted a potent and long-lasting analgesic effect in vivo when tested in a mouse model of inflammatory hyperalgesia. A single intrathecal injection of FGA-19 completely resolved hyperalgesia, being 10-fold as potent and displaying longer lasting effects than the established p38 MAPK inhibitor SB239063. FGA-19 also reversed persistent pain in a model of post-inflammatory hyperalgesia in LysM (lysozyme M)-GRK2 (G-protein-coupled-receptor kinase)(+/-) mice. These potent in vivo effects suggested p38 MAPK docking-site-targeted inhibitors as a potential novel strategy for the treatment of inflammatory pain.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Hiperalgesia/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Oxidiazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Analgésicos/química , Analgésicos/metabolismo , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/metabolismo , Anti-Inflamatórios não Esteroides/uso terapêutico , Linhagem Celular , Células Cultivadas , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Hiperalgesia/imunologia , Hiperalgesia/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Monócitos/imunologia , Monócitos/metabolismo , Oxidiazóis/química , Oxidiazóis/metabolismo , Oxidiazóis/uso terapêutico , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Distribuição Aleatória , Relação Estrutura-Atividade , Proteínas Quinases p38 Ativadas por Mitógeno/química , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
We report a highly diastereoselective synthesis of vicinal diamines by the treatment of nitroepoxides with primary amines and then a reducing agent. When using a chiral primary amine, racemic nitroepoxides are transformed into chiral diamines as a single enantiomers (>95:5 er) through a dynamic kinetic asymmetric transformation (DYKAT). The overall process is a one-pot procedure combining the exposure of nitroepoxides to chiral amines to afford diastereomeric mixtures of aminoimines and subsequent stereoselective imine reduction.
