title: Design, synthesis, SAR, and biological evaluation of highly potent benzimidazole-spaced phosphono-alpha-amino acid competitive NMDA antagonists of the AP-6 type.
abstract: A series of 2-amino-(phosphonoalkyl)-1H-benzimidazole-2-alkanoic acids was synthesized and evaluated for NMDA receptor affinity using a [3H]CPP binding assay. Functional antagonism of the NMDA receptor complex was evaluated in vitro using a stimulated [3H]TCP binding assay and in vivo by employing an NMDA-induced seizure model. Several compounds of the AP-6 type demonstrated potent and selective NMDA antagonistic activity both in vitro and in vivo. In particular, [R(-)]-2-amino-3-(5-chloro-1-phosphonomethyl-1H-benzoimidazol-2-yl)-propionic acid (1) displayed an IC(50) value of 7.1 nM in the [3H]CPP binding assay and an ED(50) value of 0.13 mg/kg (ip) in the NMDA lethality model. Compound 1, when administered intravenously as a single bolus dose of 3 mg/kg following permanent occlusion of the middle cerebral artery in the rat, reduced the volume of infarcted brain tissue by 45%. These results support a promising therapeutic potential for compound 1 as a neuroprotective agent.
authors.affiliation: Chemical Sciences and Division of Neuroscience, Wyeth-Ayerst Research, CN-8000, Princeton, New Jersey 08543-8000, USA. Baudyr@war.wyeth.com
authors.forename: R B
authors.initials: RB
authors.lastname: Baudy
authors.forename: H
authors.initials: H
authors.lastname: Fletcher
authors.forename: J P
authors.initials: JP
authors.lastname: Yardley
authors.forename: M M
authors.initials: MM
authors.lastname: Zaleska
authors.forename: D R
authors.initials: DR
authors.lastname: Bramlett
authors.forename: R P
authors.initials: RP
authors.lastname: Tasse
authors.forename: D M
authors.initials: DM
authors.lastname: Kowal
authors.forename: A H
authors.initials: AH
authors.lastname: Katz
authors.forename: J A
authors.initials: JA
authors.lastname: Moyer
authors.forename: M
authors.initials: M
authors.lastname: Abou-Gharbia
mesh_terms: D000818:Animals; D001157:Arterial Occlusive Diseases / Q000150:complications; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002340:Carotid Artery Diseases / Q000150:complications; D004353:Drug Evaluation, Preclinical; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D066298:In Vitro Techniques; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D008297:Male; D051379:Mice; D008958:Models, Molecular; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D063065:Organophosphonates; D011422:Propionates / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D011916:Rats, Inbred F344; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013237:Stereoisomerism
chemical_list: C427225:2-amino-3-(5-chloro-1-phosphonomethyl-1H-benzoimidazol-2-yl)propionic acid; D001562:Benzimidazoles; D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D063065:Organophosphonates; D011422:Propionates; D016194:Receptors, N-Methyl-D-Aspartate