RESUMO
A novel series of (E)-1-((2-(1-methyl-1H-imidazol-5-yl) quinolin-4-yl) methylene) thiosemicarbazides was discovered as potent inhibitors of IKKß. In this Letter we document our efforts at further optimization of this series, culminating in 2 with submicromolar potency in a HWB assay and efficacy in a CIA mouse model.
Assuntos
Quinase I-kappa B/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Quinolinas/química , Semicarbazidas/química , Tioureia/análogos & derivados , Animais , Cães , Feminino , Hepatócitos/metabolismo , Ensaios de Triagem em Larga Escala , Humanos , Quinase I-kappa B/metabolismo , Macaca mulatta , Masculino , Camundongos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Quinolinas/síntese química , Quinolinas/farmacocinética , Ratos , Semicarbazidas/síntese química , Semicarbazidas/farmacocinética , Relação Estrutura-Atividade , Tioureia/síntese química , Tioureia/química , Tioureia/farmacocinéticaRESUMO
A novel series of (E)-1-((2-(1-methyl-1H-imidazol-5-yl) quinolin-4-yl) methylene) thiosemicarbazides was discovered as potent inhibitors of IKKß. In this Letter we document our early efforts at optimization of the quinoline core, the imidazole and the semithiocarbazone moiety. Most potency gains came from substitution around the 6- and 7-positions of the quinoline ring. Replacement of the semithiocarbazone with a semicarbazone decreased potency but led to some measurable exposure.
Assuntos
Quinase I-kappa B/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Semicarbazidas/química , Animais , Cães , Feminino , Ensaios de Triagem em Larga Escala , Quinase I-kappa B/metabolismo , Masculino , Microssomos/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Quinolinas/química , Ratos , Semicarbazidas/síntese química , Semicarbazidas/farmacocinética , Relação Estrutura-AtividadeRESUMO
The introduction of 3-arylmethyl, 3-aryloxy and 3-arylthio moieties into a 6-methylsulfonylindole framework using rational drug design led to potent, selective COX-2 inhibitors having efficacy in a rat carrageenan air pouch model. Incorporation of a conformationally more rigid 3-aroyloxy substituent onto the 6-methylsulfonylindole scaffold led to selective, but considerably less potent COX-2 inhibitors. Variation of the hydrophilicity and size of the indole 2-substituent of 3-arylthio-6-methylsulfonylindole inhibitors led to modulation of the COX-2 human whole blood (HWB) potency and selectivity.