RESUMO
In this manuscript, we report the discovery of the substituted 2-trifluoromethyl-2H-benzopyran-3-carboxylic acids as a novel series of potent and selective cyclooxygenase-2 (COX-2) inhibitors. 5c-(S) (SD-8381) was advanced into clinical studies due to its superior in vivo potency. The high plasma protein binding (>99% bound) of 5c-(S) has resulted in a surprisingly long human half life t(1/2)=360 h.
Assuntos
Benzopiranos/química , Benzopiranos/farmacocinética , Inibidores de Ciclo-Oxigenase 2/química , Proteínas Sanguíneas/metabolismo , Ácidos Carboxílicos , Inibidores de Ciclo-Oxigenase 2/farmacocinética , Meia-Vida , Humanos , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
A structure-activity relationship study was conducted on a series of tetrahydro-beta-carboline-1-carboxylic acid analogs in order to identify the key functionality responsible for activity against the mitogen-activated protein kinase-activated protein kinase 2 enzyme (MK-2). The compounds were further evaluated for their ability to inhibit TNFalpha production in U937 cells and in vivo. These compounds represent a novel structural class of compounds capable of inhibiting MK-2 with remarkable selectivity.