RESUMO
2-aminothiazole (1) was discovered as a novel Src family kinase inhibitor template through screening of our internal compound collection. Optimization through successive structure-activity relationship iterations identified analogs 2 (Dasatinib, BMS-354825) and 12m as pan-Src inhibitors with nanomolar to subnanomolar potencies in biochemical and cellular assays. Molecular modeling was used to construct a putative binding model for Lck inhibition by this class of compounds. The framework of key hydrogen-bond interactions proposed by this model was in agreement with the subsequent, published crystal structure of 2 bound to structurally similar Abl kinase. The oral efficacy of this class of inhibitors was demonstrated with 12m in inhibiting the proinflammatory cytokine IL-2 ex vivo in mice (ED50 approximately 5 mg/kg) and in reducing TNF levels in an acute murine model of inflammation (90% inhibition in LPS-induced TNFalpha production when dosed orally at 60 mg/kg, 2 h prior to LPS administration). The oral efficacy of 12m was further demonstrated in a chronic model of adjuvant arthritis in rats with established disease when administered orally at 0.3 and 3 mg/kg twice daily. Dasatinib (2) is currently in clinical trials for the treatment of chronic myelogenous leukemia.
Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Pirimidinas/síntese química , Tiazóis/síntese química , Quinases da Família src/antagonistas & inibidores , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Artrite Experimental/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Doença Crônica , Dasatinibe , Feminino , Humanos , Técnicas In Vitro , Inflamação/sangue , Inflamação/induzido quimicamente , Interleucina-2/antagonistas & inibidores , Lipopolissacarídeos , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/antagonistas & inibidores , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Modelos Moleculares , Ligação Proteica , Pirimidinas/química , Pirimidinas/farmacologia , Ratos , Ratos Endogâmicos Lew , Relação Estrutura-Atividade , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos , Tiazóis/química , Tiazóis/farmacologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
A series of substituted 2-(aminoheteroaryl)-thiazole-5-carboxamide analogs have been synthesized as novel, potent inhibitors of the Src-family kinase p56Lck. Among them, compound 2 displayed superior in vitro potency and excellent in vivo efficacy.
Assuntos
Amidas/farmacologia , Anti-Inflamatórios/farmacologia , Inibidores Enzimáticos/farmacologia , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/antagonistas & inibidores , Tiazóis/farmacologia , Quinases da Família src/antagonistas & inibidores , Administração Oral , Amidas/síntese química , Amidas/farmacocinética , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacocinética , Artrite Experimental/terapia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Masculino , Modelos Moleculares , Estrutura Molecular , Ratos , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/farmacocinéticaRESUMO
We have identified a novel series of 1,5-imidazoquinoxalines as inhibitors of Lck with excellent potency (IC50s<5 nM) as well as good cellular activity against T-cell proliferation (IC50s<1 microM). Structure-activity studies demonstrate the requirement for the core heterocycle in addition to an optimal 2,6-disubstituted aniline group.
Assuntos
Inibidores Enzimáticos/síntese química , Imidazóis/síntese química , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/antagonistas & inibidores , Quinoxalinas/síntese química , Quinases da Família src/antagonistas & inibidores , Animais , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Imidazóis/farmacologia , Cinética , Ativação Linfocitária/efeitos dos fármacos , Modelos Moleculares , Conformação Molecular , Quinoxalinas/farmacologia , Relação Estrutura-Atividade , Linfócitos T/efeitos dos fármacos , Linfócitos T/enzimologia , Linfócitos T/imunologiaRESUMO
A novel series of 2-amino-5-carboxamidothiazoles were identified as inhibitors of Lck. Structure-activity studies demonstrate the structural requirements for potent Lck activity. Cyclopropylamide 11d is a potent Lck inhibitor having sub-micromolar activity in a PBL proliferation assay.