RESUMEN
A series of analogues of the indole-2-carboxylate GV150526, currently in clinical trials as a potential neuroprotective agent for the control of the cerebral damage after stroke onset, was designed based on previous studies dealing with the electronic features of the north-east region of the glycine binding site associated with the NMDA receptor. In particular, the substitution of the para position of the terminal phenyl ring of GV150526 with suitable hydrophilic groups resulted in the identification of a new class of glycine antagonists. These compounds exhibited nanomolar in vitro affinity to the glycine binding site, high receptor selectivity, and outstanding in vivo potency. In particular, 3-[(E)-2-[(4-ureidomethylphenyl)aminocarbonyl]ethenyl]-4, 6-dichloroindole-2-carboxylic acid was found to be highly effective in the middle cerebral artery occlusion (MCAo) model in the rat, an animal model of focal ischemia, when given both prior to and after the occlusion of the middle cerebral artery. Notably, a significant neuroprotective effect was seen in this model postischaemia, when the administration of this compound was delayed up to 6 h from the occlusion of the middle cerebral artery, further confirming the wide therapeutic window seen for GV150526A.
Asunto(s)
Isquemia Encefálica/tratamiento farmacológico , Glicinérgicos/síntesis química , Indoles/química , Indoles/síntesis química , Fármacos Neuroprotectores/síntesis química , Receptores de Glicina/antagonistas & inhibidores , Urea/análogos & derivados , Animales , Anticonvulsivantes/síntesis química , Anticonvulsivantes/farmacología , Sitios de Unión/efectos de los fármacos , Ácidos Carboxílicos , Infarto Cerebral/tratamiento farmacológico , Modelos Animales de Enfermedad , Glicina/metabolismo , Glicinérgicos/farmacología , Indoles/farmacología , Ratones , Estructura Molecular , Fármacos Neuroprotectores/farmacología , Unión Proteica , Ratas , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/metabolismo , Urea/síntesis química , Urea/farmacologíaRESUMEN
Two isomers of the hexahydro-tetraazaacenaphthylene templates (1 and 2) are presented as novel, potent, and selective corticotropin releasing factor-1 (CRF1) receptor antagonists. In this paper, we report the affinity and SAR of a series of compounds, as well as pharmacokinetic characterization of a chosen set. The anxiolitic activity of a selected example (2ba) in the rat pup vocalization model is also presented.