Design and Synthesis of [2-(8,9-Dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)- ethyl]phosphonic Acid (EAA-090), a Potent N-Methyl-d-aspartate Antagonist, via the Use of 3-Cyclobutene-1,2-dione as an Achiral α-Amino Acid Bioisostere

Abstract

The diazabicyclic amino acid phosphonate 15, [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid, was identified as a potent NMDA antagonist. It contains the alpha-amino acid bioisostere 3,4-diamino-3-cyclobutene-1,2-dione and an additional ring for conformational rigidity. Compound 15 was as potent as CGS-19755 (5) in the [3H]CPP binding assay, the stimulated [3H]TCP binding assay, and the NMDA-induced lethality model in mice. A single bolus dose of compound 15, administered intravenously following permanent occlusion of middle cerebral artery (MCA) in the rat, reduced the size of infarcted tissue by 57%. Structure-activity relationship (SAR) studies have indicated that the six- and eight-membered ring derivatives had diminished activity and that the two-carbon side chain length was optimum for NMDA receptor affinity. Substitution on the ring was found to be counterproductive in the case of sterically demanding dimethyl groups and of no consequence in the case of an H-bonding hydroxyl group. Replacement of the phosphonic acid group by either a carboxylic acid or a tetrazole group was unproductive. The potent bicyclic NMDA antagonists were synthesized efficiently by virture of their achiral nature and the ease of vinylgous amide formation from squaric acid esters. Compound 15, being a unique NMDA antagonist structural type with a favorable preclinical profile, may offer advantages over existing NMDA antagonists for the treatment of neurological disorders such as stroke and head trauma. Compound 15 is currently under clinical evaluation as a neuroprotective agent for stroke.

Effects of the N-Methyl-d-aspartate Receptor Antagonist Perzinfotel [EAA-090; [2-(8,9-Dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)-ethyl]phosphonic Acid] on Chemically Induced Thermal Hypersensitivity

“…Perzinfotel is a selective, competitive NMDA receptor antagonist with high affinity (30 nM) for the glutamate site (Kinney et al, 1998). Perzinfotel lacks activity at more than 60 other receptors, ion channels, or uptake sites (Childers et al, 2002;Sun et al, 2004).…”

“…and blocks maximal electroshock convulsions (ED 50 ϭ 4.8 mg/kg i.p.) in mice (Kinney et al, 1998;Childers et al, 2002). Perzinfotel also reverses established tactile hypersensitivity produced by L5/L6 spinal nerve ligation and chronic constriction injury of the sciatic nerve (M. R. Brandt, unpublished results), both neuropathic pain models thought to be strongly mediated by central mechanisms (Kawamata and Omote, 1996).…”

“…Previous studies have demonstrated its effectiveness in several animal stroke models and anticonvulsant models (Childers et al, 2002). Importantly, perzinfotel has an adverse effect profile superior to many other reported competitive (e.g., CGS-19755) and uncompetitive (e.g., dizocilpine) antagonists (Kinney et al, 1998;Childers et al, 2002). Given the apparent involvement of NMDA receptors in pain conditions, perzinfotel was evaluated in preclinical pain assays to determine whether the compound would have antinociceptive, antiallodynic, or antihyperalgesic effects.…”

“…Perzinfotel is a selective, competitive small molecule antagonist that blocks the actions of glutamate at the NMDA receptor (Kinney et al, 1998;Childers et al, 2002;Sun et al, 2004). Previous studies have demonstrated its effectiveness in several animal stroke models and anticonvulsant models (Childers et al, 2002).…”

Characterization of Two Novel N-Methyl-D-aspartate Antagonists: EAA-090 (2-[8,9-Dioxo-2,6-diazabicyclo [5.2.0]non-1(7)-en2-yl]ethylphosphonic Acid) and EAB-318 (R-α-Amino-5-chloro-1-(phosphonomethyl)-1H-benzimidazole-2-propanoic Acid Hydrochloride)

“…1). .0]non-1(7)-en2-yl]ethylphosphonic acid) is an NMDA antagonist with an unique squaric acid moiety (3,4-diamino-3-cyclobutene-1,2-dione) in place of a polar amino acid group (Kinney et al,1998). The squaric acid moiety is structurally similar to amino acids, but it lacks the basicity, acidity, or nucleophilicity of typical amino acids.…”