RESUMEN
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.
Asunto(s)
Bencimidazoles/administración & dosificación , Bencimidazoles/química , Bencimidazoles/síntesis química , Química Farmacéutica/métodos , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/química , Administración Oral , Animales , Bencimidazoles/farmacología , Complejo CD3/biosíntesis , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Activación de Linfocitos , Ratones , Ratones Endogámicos BALB C , Modelos Químicos , Relación Estructura-Actividad , Linfocitos T/citologíaRESUMEN
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.
Asunto(s)
Bencimidazoles/química , Bencimidazoles/síntesis química , Química Farmacéutica/métodos , Inhibidores Enzimáticos/síntesis química , Microsomas Hepáticos/metabolismo , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/química , Adenosina Trifosfato/química , Administración Oral , Sitios de Unión , Complejo CD3/química , Cristalografía por Rayos X/métodos , Diseño de Fármacos , Inhibidores Enzimáticos/química , Humanos , Concentración 50 Inhibidora , Microsomas Hepáticos/química , Relación Estructura-Actividad , Linfocitos T/metabolismoRESUMEN
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.