RESUMEN
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.
Asunto(s)
Aminas/síntesis química , Inhibidores de la Ciclooxigenasa 2/síntesis química , Éteres/síntesis química , Pirimidinas/síntesis química , Sulfonas/síntesis química , Aminas/farmacología , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Química Farmacéutica/métodos , Ciclooxigenasa 2/química , Inhibidores de la Ciclooxigenasa 2/farmacología , Modelos Animales de Enfermedad , Diseño de Fármacos , Éteres/farmacología , Humanos , Inflamación , Concentración 50 Inhibidora , Ratones , Estructura Molecular , Enfermedades Neurodegenerativas/tratamiento farmacológico , Pirimidinas/farmacología , Ratas , Sulfonas/farmacologíaRESUMEN
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.
