RESUMEN
Synthesis, modeling and structure-activity relationship of indazoles as inhibitors of Tpl2 kinase are described. From a high throughput screening effort, we identified an indazole hit compound 5 that has a single digit micromolar Tpl2 activity. Through SAR modifications at the C3 and C5 positions of the indazole, we discovered compound 31 with good potency in LANCE assay and cell-based p-Erk assay.
Asunto(s)
Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Indazoles/farmacología , Quinasas Quinasa Quinasa PAM/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Indazoles/síntesis química , Indazoles/química , Quinasas Quinasa Quinasa PAM/metabolismo , Modelos Moleculares , Estructura Molecular , Monocitos/enzimología , Monocitos/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Discovery efforts were focused on identifying a non-nucleoside antiviral for treating infections caused by human cytomegalovirus (HCMV) with equal or better potency and diminished toxicity compared to current therapeutics. This Letter describes the HCMV DNA polymerase inhibition and in vitro antiviral activity of various 2-aryl-2-hydroxy ethylamine substituted 1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamides.