RESUMO
The development of a series of novel 4-substituted-2-aminopyrimidines as inhibitors of c-Jun N-terminal kinases is described. The synthesis, in vitro inhibitory values for JNK1, and the in vitro inhibitory value for a c-Jun cellular assay are discussed. Optimization of microsomal clearance led to the identification of 9c, whose kinase selectivity is reported.
Assuntos
Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacologia , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Proteína Quinase 8 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 8 Ativada por Mitógeno/metabolismo , Relação Estrutura-AtividadeRESUMO
A new one-pot nitration employing tetramethylammonium nitrate and trifluoromethanesulfonic anhydride in dichloromethane to provide a ready source of the nitronium triflate nitrating agent is presented. Rapid and selective nitration with a variety of aromatic and heteroaromatic substrates is achieved resulting in the synthesis of several novel organic compounds. A distinct advantage is the removal of undesired byproducts by aqueous workup. This very mild nitration permits large-scale syntheses and gives high isolated product yields that often require no further purification. This tetramethylammonium nitrate-based nitration also has been applied to microwave-assisted conditions, and the results with several compounds are outlined.
