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
We describe herein the medicinal chemistry approach which led to the discovery of a novel pyridine-3-carboxamide series of CB(2) receptor agonists. The SAR of this new template was evaluated and culminated in the identification of analogue 14a which demonstrated efficacy in an in vivo model of inflammatory pain.
