RESUMEN

(E)-3-(2-Carboxy-2-phenylvinyl)-4,6-dichloro-1H-indole-2-carboxylic acid, 1, is a potent and selective antagonist of the glycine site of the N-methyl-d-aspartate (NMDA) receptor. Using 3D comparative molecular field analysis (CoMFA) to guide the synthetic effort, a series of aryl diacid analogues of 1 were synthesized to optimize in vivo potency, duration of action, and binding activity. It was found that the incorporation of a substituted aromatic with an electron withdrawing group or a heterocyclic group at the 2-position of the 3-propenyl moiety of 1 gave compounds with better affinity and potency in the murine stroke model. Ultimately this led to the discovery of 3-[2-(3-aminophenyl)-2-carboxyvinyl]-4,6-dichloro-1H-indole-2-carboxylic acid, 19, as a new potent selective glycine-site NMDA receptor antagonist.

Asunto(s)

Ácidos Carboxílicos/síntesis química , Glicina/metabolismo , Indoles/química , Fenilacetatos/química , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/química , Animales , Anticonvulsivantes/síntesis química , Anticonvulsivantes/química , Anticonvulsivantes/farmacología , Sitios de Unión , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacología , GMP Cíclico/biosíntesis , Técnicas In Vitro , Indoles/síntesis química , Indoles/farmacología , Masculino , Ratones , Ratones Endogámicos DBA , Modelos Moleculares , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/farmacología , Fenilacetatos/síntesis química , Fenilacetatos/farmacología , Relación Estructura-Actividad Cuantitativa , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Convulsiones/etiología , Convulsiones/prevención & control , Estereoisomerismo , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/patología