RESUMO
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.
Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Artrite/tratamento farmacológico , Benzimidazóis/síntese química , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Pirimidinonas/síntese química , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Benzimidazóis/química , Benzimidazóis/farmacologia , Cristalografia por Raios X , Modelos Animais de Doenças , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Ativação Enzimática/efeitos dos fármacos , Feminino , Injeções Intradérmicas , Interleucina-2/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Pirimidinonas/química , Pirimidinonas/farmacologia , Ratos , Ratos Endogâmicos Lew , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Estereoisomerismo , Relação Estrutura-Atividade , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismoRESUMO
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.
Assuntos
Aminopiridinas/síntese química , Anti-Inflamatórios/síntese química , Carbamatos/síntese química , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/antagonistas & inibidores , Pirimidinas/síntese química , Administração Oral , Aminopiridinas/química , Aminopiridinas/farmacologia , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Disponibilidade Biológica , Carbamatos/química , Carbamatos/farmacologia , Cristalografia por Raios X , Humanos , Técnicas In Vitro , Células Jurkat , Ativação Linfocitária , Teste de Cultura Mista de Linfócitos , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Estrutura Molecular , Pirimidinas/química , Pirimidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologiaRESUMO
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.
Assuntos
Proteína Tirosina Quinase p56(lck) Linfócito-Específica/antagonistas & inibidores , Piridinas/síntese química , Piridinas/farmacocinética , Aminas/síntese química , Aminas/farmacocinética , Animais , Humanos , Concentração Inibidora 50 , Farmacocinética , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
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.