RESUMO
Imidazo[1,2-a]pyridine derivatives were designed, synthesized, and evaluated as inhibitors of the apoptosis signal-regulating kinase 1 (ASK1). These were based on a benzothiazole derivative that was discovered from high-throughput screening of our compound library. As a result, we identified potent, selective, and orally bioavailable ASK1 inhibitors for wide range of therapeutic targets.
Assuntos
Desenho de Fármacos , MAP Quinase Quinase Quinase 5/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Animais , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Ensaios de Triagem em Larga Escala , MAP Quinase Quinase Quinase 5/metabolismo , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Piridinas/síntese química , Piridinas/química , Ratos , Relação Estrutura-AtividadeRESUMO
Triarylmethanols are effectively dehydroarylated and reacted with some unsaturated compounds by using an appropriate palladium catalyst system such as Pd(OAc)2-P(1-Nap)3 (1-Nap = 1-naphthyl) to give the corresponding arenes and hydroarylation products, respectively, along with diaryl ketones.
RESUMO
The palladium-catalyzed arylation of alpha,alpha-disubstituted arylmethanols with aryl halides proceeds not only via C-H bond cleavage at the ortho-position, but also via cleavage of the sp(2)-sp(3) C-C bond with the liberation of ketones (beta-carbon elimination) to give the corresponding biaryls. Both reactions appear to occur through common arylpalladium(II) alcoholate intermediates. The results of systematic studies with respect to which C-C or C-H bond is preferentially cleaved in the arylation are reported. Among the important findings is the selective elimination of ortho-substituted aryl groups even from aryl(diphenyl)methanols due to steric reasons. Thus, various biaryls having ortho-substituents can be produced efficiently by treatment of the corresponding aryl(diphenyl or dimethyl)methanols with aryl bromides and chlorides.