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
We have recently reported the discovery of a novel class of glucocorticoid receptor (GR) antagonists, exemplified by 3, containing a 1,2-dihydroquinoline molecular scaffold. Further SAR studies of these antagonists uncovered chemical modifications conveying agonist functional activity to this series. These agonists exhibit good GR binding affinity and are selective against other nuclear hormone receptors.
Asunto(s)
Quinolinas/química , Quinolinas/farmacología , Receptores de Glucocorticoides/agonistas , Quinolinas/metabolismo , Receptores de Glucocorticoides/metabolismo , Relación Estructura-ActividadRESUMEN
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.