RESUMO
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.
Assuntos
Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Indazóis/farmacologia , MAP Quinase Quinase Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Indazóis/síntese química , Indazóis/química , MAP Quinase Quinase Quinases/metabolismo , Modelos Moleculares , Estrutura Molecular , Monócitos/enzimologia , Monócitos/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
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.