RESUMEN
Lck, or lymphocyte specific kinase, is a cytoplasmic tyrosine kinase of the Src family expressed in T-cells and NK cells. Genetic evidence from knockout mice and human mutations demonstrates that Lck kinase activity is critical for T-cell receptor-mediated signaling, leading to normal T-cell development and activation. A small molecule inhibitor of Lck is expected to be useful in the treatment of T-cell-mediated autoimmune and inflammatory disorders and/or organ transplant rejection. In this paper, we describe the structure-guided design, synthesis, structure-activity relationships, and pharmacological characterization of 2-amino-6-phenylpyrimido[5',4':5,6]pyrimido[1,2- a]benzimidazol-5(6 H)-ones, a new class of compounds that are potent inhibitors of Lck. The most promising compound of this series, 6-(2,6-dimethylphenyl)-2-((4-(4-methyl-1-piperazinyl)phenyl)amino)pyrimido[5',4':5,6]pyrimido-[1,2- a]benzimidazol-5(6 H)-one ( 25), exhibits potent inhibition of Lck kinase activity. This activity translates into inhibition of in vitro cell-based assays and in vivo models of T-cell activation and arthritis, respectively.
Asunto(s)
Antiinflamatorios no Esteroideos/síntesis química , Artritis/tratamiento farmacológico , Bencimidazoles/síntesis química , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/síntesis química , Pirimidinonas/síntesis química , Administración Oral , Animales , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Bencimidazoles/química , Bencimidazoles/farmacología , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Activación Enzimática/efectos de los fármacos , Femenino , Inyecciones Intradérmicas , Interleucina-2/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinonas/química , Pirimidinonas/farmacología , Ratas , Ratas Endogámicas Lew , Ratas Sprague-Dawley , Reproducibilidad de los Resultados , Estereoisomerismo , Relación Estructura-Actividad , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismoRESUMEN
4-Amino-5,6-biaryl-furo[2,3-d]pyrimidines were identified as potent non-selective inhibitors of Lck. A novel, divergent, and practical synthetic route was developed to access derivatives from bifunctional intermediates. Lead optimization was guided by X-ray crystallographic data, and preliminary SAR led to the identification of compounds with improved cellular potency and selectivity.
Asunto(s)
Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/antagonistas & inhibidores , Pirimidinas/síntesis química , Pirimidinas/farmacocinética , Relación Estructura-Actividad Cuantitativa , Animales , Antiinflamatorios/síntesis química , Humanos , Concentración 50 Inhibidora , Interleucina-2/metabolismo , Prueba de Cultivo Mixto de Linfocitos , Linfocitos/efectos de los fármacos , Farmacocinética , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Ratas , Ratas Sprague-DawleyRESUMEN
2,3-Diarylfuro[2,3-b]pyridine-4-amines are a novel class of potent and selective inhibitors of Lck. The discovery, synthesis, and structure activity relationships of this series of inhibitors are reported. The most promising compounds were also profiled to deduce their pharmacokinetic properties.
Asunto(s)
Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/antagonistas & inhibidores , Piridinas/síntesis química , Piridinas/farmacocinética , Aminas/síntesis química , Aminas/farmacocinética , Animales , Humanos , Concentración 50 Inhibidora , Farmacocinética , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
The lymphocyte-specific kinase (Lck) is a cytoplasmic tyrosine kinase of the Src family expressed in T cells and NK cells. Genetic evidence in both mice and humans demonstrates that Lck kinase activity is critical for signaling mediated by the T cell receptor (TCR), which leads to normal T cell development and activation. A small molecule inhibitor of Lck is expected to be useful in the treatment of T cell-mediated autoimmune and inflammatory disorders and/or organ transplant rejection. In this paper, we describe the synthesis, structure-activity relationships, and pharmacological characterization of 2-aminopyrimidine carbamates, a new class of compounds with potent and selective inhibition of Lck. The most promising compound of this series, 2,6-dimethylphenyl 2-((3,5-bis(methyloxy)-4-((3-(4-methyl-1-piperazinyl)propyl)oxy)phenyl)amino)-4-pyrimidinyl(2,4-bis(methyloxy)phenyl)carbamate (43) exhibits good activity when evaluated in in vitro assays and in an in vivo model of T cell activation.