RESUMEN
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.
Asunto(s)
Benzamidas/síntesis química , Benzamidas/farmacología , Diseño de Fármacos , Antagonistas de los Receptores Histamínicos H3/síntesis química , Antagonistas de los Receptores Histamínicos H3/farmacología , Pirrolidinas/síntesis química , Pirrolidinas/farmacología , Animales , Benzamidas/química , Benzamidas/farmacocinética , Encéfalo/metabolismo , Trastornos del Conocimiento/tratamiento farmacológico , Trastornos del Conocimiento/fisiopatología , Diabetes Insípida/tratamiento farmacológico , Diabetes Insípida/metabolismo , Modelos Animales de Enfermedad , Antagonistas de los Receptores Histamínicos H3/química , Antagonistas de los Receptores Histamínicos H3/farmacocinética , Antígenos de Histocompatibilidad/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intracelular , Microsomas Hepáticos/metabolismo , Terapia Molecular Dirigida , Unión Proteica , Pirrolidinas/química , Pirrolidinas/farmacocinética , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Proteínas de Motivos TripartitosRESUMEN
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.