Design, synthesis, SAR, and biological evaluation of highly potent benzimidazole-spaced phosphono-alpha-amino acid competitive NMDA antagonists of the AP-6 type

Citation
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
Citations number
33
Categorie Soggetti
Chemistry & Analysis
Journal title
JOURNAL OF MEDICINAL CHEMISTRY
ISSN journal
00222623 → ACNP
Volume
44
Issue
10
Year of publication
2001
Pages
1516 - 1529
Database
ISI
SICI code
0022-2623(20010510)44:10<1516:DSSABE>2.0.ZU;2-U
Abstract
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.