RESUMEN
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.
Asunto(s)
Diseño de Fármacos , Indoles/síntesis química , Proteína Quinasa 14 Activada por Mitógenos/antagonistas & inhibidores , Piperazinas/síntesis química , Inhibidores de Proteínas Quinasas/síntesis química , Animales , Perros , Haplorrinos , Humanos , Indoles/farmacocinética , Proteína Quinasa 14 Activada por Mitógenos/metabolismo , Piperazina , Piperazinas/farmacocinética , Unión Proteica/efectos de los fármacos , Unión Proteica/fisiología , Inhibidores de Proteínas Quinasas/farmacocinética , Estructura Secundaria de Proteína , RatasRESUMEN
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.
Asunto(s)
Derivados del Benceno/farmacología , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/antagonistas & inhibidores , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Indoles/farmacología , Maleimidas/farmacología , Adenosina Trifosfato/metabolismo , Derivados del Benceno/síntesis química , Sitios de Unión , Inhibidores Enzimáticos/síntesis química , Interacciones Hidrofóbicas e Hidrofílicas , Indoles/síntesis química , Maleimidas/síntesis química , Modelos Químicos , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
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.
Asunto(s)
Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/antagonistas & inhibidores , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Pirimidinas/farmacología , Adenosina Trifosfato/metabolismo , Unión Competitiva , Inhibidores Enzimáticos/síntesis química , Modelos Químicos , Pirimidinas/química , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
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.
Asunto(s)
Derivados del Benceno/farmacología , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/antagonistas & inhibidores , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Indoles/farmacología , Maleimidas/farmacología , Adenosina Trifosfato/metabolismo , Derivados del Benceno/síntesis química , Sitios de Unión , Inhibidores Enzimáticos/síntesis química , Indoles/síntesis química , Maleimidas/síntesis química , Modelos Químicos , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
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.
Asunto(s)
Aminas/farmacología , Derivados del Benceno/farmacología , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/antagonistas & inhibidores , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Indoles/farmacología , Maleimidas/farmacología , Adenosina Trifosfato/metabolismo , Aminas/química , Derivados del Benceno/síntesis química , Sitios de Unión , Inhibidores Enzimáticos/síntesis química , Indoles/síntesis química , Maleimidas/síntesis química , Modelos Químicos , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
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.
Asunto(s)
Antiinflamatorios/síntesis química , Compuestos Heterocíclicos/síntesis química , Indoles/síntesis química , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Animales , Antiinflamatorios/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Compuestos Heterocíclicos/farmacología , Humanos , Indoles/farmacología , Concentración 50 Inhibidora , Relación Estructura-Actividad , Proteínas Quinasas p38 Activadas por MitógenosRESUMEN
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.