RESUMO
Derivatives of the 4-fluorobenzyl dimethylpiperazine-indole class of p38alpha MAP kinase inhibitors are described. Biological evaluation of these compounds focused on maintaining activity while improving pharmacokinetic (PK) properties. Improved properties were observed for structures bearing substitutions on the benzylic methylene.
Assuntos
Desenho de Fármacos , Indóis/síntese química , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Piperazinas/síntese química , Inibidores de Proteínas Quinases/síntese química , Animais , Cães , Haplorrinos , Humanos , Indóis/farmacocinética , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Piperazina , Piperazinas/farmacocinética , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/fisiologia , Inibidores de Proteínas Quinases/farmacocinética , Estrutura Secundária de Proteína , RatosRESUMO
A family of aryl-substituted maleimides was prepared and studied for their activity against calmodulin dependant kinase. Inhibitory activities against the enzyme ranged from 34nM to >20microM and were dependant upon both the nature of the aryl group and the hydrogen bond donating potential of the maleimide ring. Key interactions with the kinase ATP site and hinge region were found to be consistent with homology modeling predictions.
Assuntos
Derivados de Benzeno/farmacologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/antagonistas & inibidores , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Indóis/farmacologia , Maleimidas/farmacologia , Trifosfato de Adenosina/metabolismo , Derivados de Benzeno/síntese química , Sítios de Ligação , Inibidores Enzimáticos/síntese química , Indóis/síntese química , Maleimidas/síntese química , Modelos Químicos , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
A family of aryl-substituted maleimides was prepared and studied for their activity against calmodulin-dependant kinase. Inhibitory activities against the enzyme ranged from 34nM to >20microM and were dependant upon both the nature of the aryl group and the tether joining the basic amine to the indolyl maleimide core. Key interactions with the kinase ATP site and hinge region, predicted by homology modeling, were confirmed.
Assuntos
Aminas/farmacologia , Derivados de Benzeno/farmacologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/antagonistas & inibidores , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Indóis/farmacologia , Maleimidas/farmacologia , Trifosfato de Adenosina/metabolismo , Aminas/química , Derivados de Benzeno/síntese química , Sítios de Ligação , Inibidores Enzimáticos/síntese química , Indóis/síntese química , Maleimidas/síntese química , Modelos Químicos , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
A family of aryl-substituted maleimides was prepared and studied for their activity against calmodulin dependant kinase. Inhibitory activities against the enzyme ranged from 10nM to >20microM and were dependant upon both the nature of the aryl group and the tether joining the basic amine to the indolyl maleimide core of the inhibitors. Key interactions with the kinase ATP site and hinge region, predicted by homology modeling, were confirmed.
Assuntos
Derivados de Benzeno/farmacologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/antagonistas & inibidores , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Indóis/farmacologia , Maleimidas/farmacologia , Trifosfato de Adenosina/metabolismo , Derivados de Benzeno/síntese química , Sítios de Ligação , Inibidores Enzimáticos/síntese química , Interações Hidrofóbicas e Hidrofílicas , Indóis/síntese química , Maleimidas/síntese química , Modelos Químicos , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
Non-ATP competitive pyrimidine-based inhibitors of CaMKIIdelta were identified. Computational studies were enlisted to predict the probable mode of binding. The results of the computational studies led to the design of ATP competitive inhibitors with optimized hinge interactions. Inhibitors of this class possessed improved enzyme and cellular activity compared to early leads.
Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/antagonistas & inibidores , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Pirimidinas/farmacologia , Trifosfato de Adenosina/metabolismo , Ligação Competitiva , Inibidores Enzimáticos/síntese química , Modelos Químicos , Pirimidinas/química , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
Two new alkaloids, polycarpine (1) and N,N-didesmethylgrossularine-1 (4), have been isolated from extracts of the ascidian Polycarpa aurata collected in Chuuk, Federated States of Micronesia. Three degradation products of 1 were also isolated. The structures of 1, 2, and 4 were determined by X-ray crystallography. The dimeric disulfide 1 inhibited the enzyme inosine monophosphate dehydrogenase, but the inhibition could be reversed by addition of excess dithiothreitol suggesting that 1 reacts with sulfhydryl groups on the enzyme.
RESUMO
p38alpha Mitogen Activated Protein Kinase (MAP kinase) is an intracellular soluble serine threonine kinase. p38alpha kinase is activated in response to cellular stresses, growth factors and cytokines such as interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-alpha). The central role of p38alpha activation in settings of both chronic and acute inflammation has led efforts to find inhibitors of this enzyme as possible therapies for diseases such as rheumatoid arthritis, where p38alpha activation is thought to play a causal role. Herein, we report structure-activity relationship studies on a series of indole-based heterocyclic inhibitors that led to the design and identification of a new class of p38alpha inhibitors.