RESUMO
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.
Assuntos
Aminas/síntese química , Inibidores de Ciclo-Oxigenase 2/síntese química , Éteres/síntese química , Pirimidinas/síntese química , Sulfonas/síntese química , Aminas/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Química Farmacêutica/métodos , Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Modelos Animais de Doenças , Desenho de Fármacos , Éteres/farmacologia , Humanos , Inflamação , Concentração Inibidora 50 , Camundongos , Estrutura Molecular , Doenças Neurodegenerativas/tratamento farmacológico , Pirimidinas/farmacologia , Ratos , Sulfonas/farmacologiaRESUMO
Optimization of a pyrrolidine-based template using structure-based design and physicochemical considerations has provided a development candidate 20b (3082) with submicromolar potency in the HCV replicon and good pharmacokinetic properties.