RESUMO
On the basis of the previously reported benzimidazole 1,3'-bipyrrolidine benzamides (1), a series of related pyrrolidin-3-yl-N-methylbenzamides were synthesized and evaluated as H(3) receptor antagonists. In particular, compound 32 exhibits potent H(3) receptor binding affinity, improved pharmaceutical properties and a favorable in vivo profile.
Assuntos
Benzamidas/síntese química , Benzamidas/farmacologia , Desenho de Fármacos , Antagonistas dos Receptores Histamínicos H3/síntese química , Antagonistas dos Receptores Histamínicos H3/farmacologia , Pirrolidinas/síntese química , Pirrolidinas/farmacologia , Animais , Benzamidas/química , Benzamidas/farmacocinética , Encéfalo/metabolismo , Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/fisiopatologia , Diabetes Insípido/tratamento farmacológico , Diabetes Insípido/metabolismo , Modelos Animais de Doenças , Antagonistas dos Receptores Histamínicos H3/química , Antagonistas dos Receptores Histamínicos H3/farmacocinética , Antígenos de Histocompatibilidade/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Microssomos Hepáticos/metabolismo , Terapia de Alvo Molecular , Ligação Proteica , Pirrolidinas/química , Pirrolidinas/farmacocinética , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Proteínas com Motivo TripartidoRESUMO
Previous studies with perzinfotel (1), a potent, selective, competitive NMDA receptor antagonist, showed it to be efficacious in inflammatory and neuropathic pain models. To increase the low oral bioavailability of 1 (3-5%), prodrug derivatives (3a-h) were synthesized and evaluated. The oxymethylene-spaced diphenyl analogue 3a demonstrated good stability at acidic and neutral pH, as well as in simulated gastric fluid. In rat plasma, 3a was rapidly converted to 1 via 2a. Pharmacokinetic studies indicated that the amount of systemic exposure of 1 produced by a 10 mg/kg oral dose of 3a was 2.5-fold greater than that produced by a 30 mg/kg oral dose of 1. Consistent with these results, 3a was significantly more potent and had a longer duration of activity than 1 following oral administration in a rodent model of inflammatory pain. Taken together, these results demonstrate that an oxymethylene-spaced prodrug approach increased the bioavailability of 1.