RESUMEN
A novel class of Janus tyrosine kinase 3 (JAK3) inhibitors based on a 2-benzimidazoylpurinone core structure is described. Through substitution of the benzimidazoyl moiety and optimization of the N-9 substituent of the purinone, compound 24 was identified incorporating a chroman-based functional group. Compound 24 shows excellent kinase activity, good oral bioavailability and demonstrates efficacy in an acute mechanistic mouse model through inhibition of interleukin-2 (IL-2) induced interferon-gamma (INF-gamma) production.
Asunto(s)
Bencimidazoles/farmacología , Inhibidores Enzimáticos/farmacología , Janus Quinasa 3/antagonistas & inhibidores , Purinas/farmacología , Animales , Bencimidazoles/síntesis química , Bencimidazoles/química , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Interferón gamma/biosíntesis , Interleucina-2/antagonistas & inhibidores , Ratones , Modelos Animales , Modelos Moleculares , Estructura Molecular , Purinas/síntesis química , Purinas/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
An imidazolylpyrimidine was identified in a CXCR2 chemokine receptor antagonist screen and was optimized for potency, in vitro metabolic stability, and oral bioavailability. It was found that subtle structural modification within the series affected the oral bioavailability. Potent and orally available CXCR2 antagonists are herein reported.
Asunto(s)
Pirimidinas/farmacología , Receptores de Interleucina-8B/antagonistas & inhibidores , Administración Oral , Animales , Células CHO , Cricetinae , Humanos , Pruebas de Sensibilidad Microbiana , Pirimidinas/administración & dosificación , Pirimidinas/farmacocinética , Proteínas Recombinantes/antagonistas & inhibidoresRESUMEN
Structure-activity studies on benzamide 1 obtained from library screening led to the discovery of a novel series of potent and selective glycine transporter type-2 inhibitors.