Design, synthesis, SAR, and biological evaluation of highly potent benzimidazole-spaced phosphono-alpha-amino acid competitive NMDA antagonists of the AP-6 type
Rb. Baudy et al., Design, synthesis, SAR, and biological evaluation of highly potent benzimidazole-spaced phosphono-alpha-amino acid competitive NMDA antagonists of the AP-6 type, J MED CHEM, 44(10), 2001, pp. 1516-1529
A series of 2-amino-(phosphonoalkyl)-1H-benzimidazole-2-alkanoic acids was
synthesized and evaluated for NR NMDA receptor affinity using a [H-3]CPP bi
nding assay. Functional antagonism of the NMDA receptor complex was evaluat
ed in vitro using a stimulated [H-3]TCP binding assay and in vivo by employ
ing an NMDA-induced seizure model. Several compounds of the AP-6 type demon
strated potent and selective NMDA antagonistic activity both in vitro and i
n vivo. In particular, [R(-)]-2-amino-3-(5-chloro-1-phosphonomethyl-1H-benz
oimidazol-2-yl)- propionic acid (1) displayed an IC50 value of 7.1 nM in th
e [3H] Cpp binding assay and an ED50 value of 0.13 mg/kg (ip) in the NMDA l
ethality model. Compound 1, when administered intravenously as a single bol
us dose of 3 mg/kg following permanent; occlusion of the middle cerebral ar
tery in the rat, reduced the volume of infarcted brain tissue by 45%. These
results support a promising therapeutic potential for compound 1 as a neur
oprotective agent.