RESUMO
The lead optimization of a series of potent azaindole IKK2 inhibitors is described. Optimization of the human whole blood activity and selectivity over IKK1 in parallel led to the discovery of 16, a potent and selective IKK2 inhibitor showing good efficacy in a rat model of neutrophil activation.
Assuntos
Quinase I-kappa B/antagonistas & inibidores , Indóis/química , Inibidores de Proteínas Quinases/química , Animais , Disponibilidade Biológica , Modelos Animais de Doenças , Meia-Vida , Humanos , Quinase I-kappa B/metabolismo , Indóis/síntese química , Indóis/farmacocinética , Pulmão/metabolismo , Neutrófilos/imunologia , Neutrófilos/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
The synthesis and SAR of a novel series of IKK2 inhibitors are described. Modification around the hinge binding region of the 7-azaindole led to a series of potent and selective inhibitors with good cellular activity.
Assuntos
Química Farmacêutica/métodos , Quinase I-kappa B/antagonistas & inibidores , Indóis/síntese química , Indóis/farmacologia , Trifosfato de Adenosina/química , Sítios de Ligação , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Modelos Químicos , Modelos Moleculares , Estrutura Molecular , Ligação Proteica , Relação Estrutura-Atividade , Sulfonamidas/químicaRESUMO
A novel series of [4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)-2-pyrimidine-based cyclooxygenase-2 (COX-2) inhibitors, which have a different arrangement of substituents compared to the more common 1,2-diarylheterocycle based molecules, have been discovered. For example, 2-(butyloxy)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine (47), a member of the 2-pyrimidinyl ether series, has been shown to be a potent and selective inhibitor with a favourable pharmacokinetic profile, high brain penetration and good efficacy in rat models of hypersensitivity.