RESUMO
A series of novel 5-aminomethyl-1H-benzimidazole based inhibitors of Itk were prepared. Structure-activity relationships, selectivity and cell activity are reported for this series. Compound 2, a potent and selective antagonist of Itk, inhibited anti-CD3 antibody induced IL-2 production in vivo in mice.
Assuntos
Benzimidazóis/administração & dosagem , Benzimidazóis/química , Benzimidazóis/síntese química , Química Farmacêutica/métodos , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/química , Administração Oral , Animais , Benzimidazóis/farmacologia , Complexo CD3/biossíntese , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos BALB C , Modelos Químicos , Relação Estrutura-Atividade , Linfócitos T/citologiaRESUMO
Previously, we reported a series of novel benzimidazole based Itk inhibitors that exhibited excellent enzymatic potency and selectivity but low microsomal stability. Employing a structure based approach a new series of inhibitors with comparable potency and selectivity to the original series and with a potential for improved microsome stability was identified.
Assuntos
Benzimidazóis/química , Benzimidazóis/síntese química , Química Farmacêutica/métodos , Inibidores Enzimáticos/síntese química , Microssomos Hepáticos/metabolismo , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/química , Trifosfato de Adenosina/química , Administração Oral , Sítios de Ligação , Complexo CD3/química , Cristalografia por Raios X/métodos , Desenho de Fármacos , Inibidores Enzimáticos/química , Humanos , Concentração Inibidora 50 , Microssomos Hepáticos/química , Relação Estrutura-Atividade , Linfócitos T/metabolismoRESUMO
An uHTS campaign was performed to identify selective inhibitors of PKC-theta. Initial triaging of the hit set based on selectivity and historical analysis led to the identification of 2,4-diamino-5-nitropyrimidines as potent and selective PKC-theta inhibitors. A homology model and initial SAR is presented demonstrating that a 2-arylalkylamino substituent in conjunction with suitable 4-diamino substituent are essential for achieving selectivity over many kinases. Additional hit to lead profiling is presented on selected compounds.