RESUMO
A gamma-carboline series of cysLT(1) receptor antagonists has been prepared. Some of the compounds show good potencies both, in vitro and in vivo, compared to the standard compounds.
Assuntos
Carbolinas/química , Química Farmacêutica/métodos , Antagonistas de Leucotrienos/síntese química , Receptores de Leucotrienos/química , Administração Oral , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Desenho de Fármacos , Cobaias , Humanos , Concentração Inibidora 50 , Antagonistas de Leucotrienos/farmacologia , Modelos Químicos , Relação Estrutura-Atividade , Fatores de TempoRESUMO
A series of 2-phenylpyran-4-ones were prepared and evaluated for their ability to inhibit cyclooxygenase-2 (COX-2). Extensive structure-activity relationship work was carried out within this series, and a number of potent and selective COX-2 inhibitors were identified. Compounds having a p-methylsulfone group at the 2-phenyl ring showed the best COX-2 inhibitory activity. The introduction of a substituted phenoxy ring at position 3 enhanced both the in vitro and in vivo activity within the series. A selected group of 3-phenoxypyran-4-ones exhibited excellent activity in an experimental model of pyresis. The in vivo antiinflammatory activity of these compounds was confirmed with the evaluation of their antiarthritic and analgesic effectiveness. Moreover, their pharmacokinetic profile in rats is compatible with a once a day administration by oral route in humans. Within this novel series, compounds 21, 31, 34, and 35 have been selected for further preclinical and clinical evaluation.