RESUMO
Pyrrolo[2,1-f][1,2,4]triazine based inhibitors of p38α have been prepared exploring functional group modifications at the C6 position. Incorporation of aryl and heteroaryl ketones at this position led to potent inhibitors with efficacy in in vivo models of acute and chronic inflammation.
Assuntos
Anti-Inflamatórios/química , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Pirróis/química , Triazinas/química , Administração Oral , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Artrite/tratamento farmacológico , Sítios de Ligação , Cristalografia por Raios X , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Feminino , Camundongos , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Estrutura Terciária de Proteína , Ratos , Relação Estrutura-Atividade , Triazinas/farmacologia , Triazinas/uso terapêuticoRESUMO
The synthesis, structure-activity relationships (SAR) and biological evaluation of thiazole based tricyclic inhibitors of IKK2 are described. Compound 9 was determined to be orally efficacious in a murine model of rheumatoid arthritis.
Assuntos
Artrite Reumatoide/tratamento farmacológico , Quinase I-kappa B/antagonistas & inibidores , Imidazóis/química , Inibidores de Proteínas Quinases/química , Piridinas/química , Tiazóis/química , Animais , Modelos Animais de Doenças , Cães , Avaliação Pré-Clínica de Medicamentos , Feminino , Quinase I-kappa B/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/farmacocinética , Piridinas/uso terapêutico , Ratos , Relação Estrutura-AtividadeRESUMO
OBJECTIVE: To observe the cerebral activating effects of needling at Waiguan (SJ5) versus SJ5 plus Yanglingquan (GB34) points in young healthy volunteers based on the hypothesis of "needling effect of combined acupuncture points relates to the brain activation". METHODS: Sixteen healthy volunteers were randomly divided into SJ5 group and SJ5 plus GB34 group, and there were 8 volunteers in each group. The volunteers in the two groups received needling at corresponding points on the right hand or foot respectively. Nuclear magnetic resonance (1.5T, GE Corporation) was used for functional magnetic resonance imaging (fMRI) of the brain before and during the needling, and the obtained experimental data in the regional brain were processed and analyzed by the method of region of interest (ROI). RESULTS: The ROI activation induced by needling of SJ5 or SJ5 plus GB34 was all relatively concentrated (activation rate more than 4 or activation point more than 10) on bilateral frontal and parietal lobes. There were no significant differences in ROI activation rates of brain regions between the two groups. ROI activation points showed that needling at SJ5 could activate the right cerebellum specifically (P < 0.05, vs SJ5 plus GB34), while needling at SJ5 plus GB34 could activate the left parietal and occipital lobes and bilateral basal ganglion more effectively than activate the other brain regions (P < 0.05, vs SJ5). ROI activation strength showed that needling at SJ5 plus GB34 could more strongly activate the right cerebellum (P < 0.05, vs SJ5). CONCLUSION: Based on fMRI data, a kind of acupuncture point combination of SJ5 and GB34 within the hand-foot Shaoyang meridians, could improve the motor and sensory dysfunctions and equilibrium disturbance. The effect of combined acupuncture points was proved by cerebral activity initially.