RESUMO
Many years of work have been invested in the identification of potent and selective COX-2 inhibitors for the treatment of chronic inflammatory pain. One issue faced by workers is the balance between the lipophilicity required for potent enzyme inhibition and the physical properties necessary for drug absorption and distribution in vivo. Frequently approaches to reduce lipophilicity through introduction of polar functionality is hampered by highly challenging chemistry to prepare key molecules. We have complemented traditional synthetic chemistry with a biotransformations approach which efficiently provided access to an array of key target molecules.
Assuntos
Inibidores de Ciclo-Oxigenase 2/síntese química , Biotransformação , Química Farmacêutica/métodos , Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Desenho de Fármacos , Humanos , Inflamação/tratamento farmacológico , Concentração Inibidora 50 , Modelos Químicos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
GW406381 (8), currently undergoing clinical evaluation for the treatment of inflammatory pain is a member of a novel series of 2,3-diaryl-pyrazolo[1,5-b]pyridazine based cyclooxygenase-2 (COX-2) inhibitors, which have been shown to be highly potent and selective. Several examples of the series, in addition to possessing favourable pharmacokinetic profiles and analgesic activity in vivo, have also demonstrated relatively high brain penetration in the rat compared with the clinically available compounds, which may ultimately prove beneficial in the treatment of pain.