DESIGN AND SYNTHESIS OF AZABICYCLO[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 ALPHA-AMINO-ACID BIOISOSTERE

The diazabicyclic amino acid phosphonate 15, azabicyclo[5.2.0]non-1(7) -en-2-yl)ethyl]phosphonic acid, was identified as a potent NMDA antago nist. It contains the alpha-amino acid bioisostere 3,4-diamino-3-cyclo butene-1,2-dione and an additional ring for conformational rigidity. C ompound 15 was as potent as CGS-19755 (5) in the [H-3]CPP binding assa y, the stimulated [H-3]TCP binding assay, and the NMDA-induced lethali ty model in mice. A single bolus dose of compound 15, administered int ra venously following permanent occlusion of middle cerebral artery (M CA) in the rat, reduced the size of infarcted tissue by 57%. Structure -activity relationship (SAR) studies have indicated that the six-and e ight-membered ring derivatives had diminished activity and that the tw o-carbon side chain length was optimum for NMDA receptor affinity. Sub stitution on the ring was found to be counterproductive in the case of sterically demanding dimethyl groups and of no consequence in the cas e of an H-bonding hydroxyl group. Replacement of the phosphonic acid g roup 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 forma tion from squaric acid esters. Compound 15, being a unique NMDA antago nist structural type with a favorable preclinical profile, may offer a dvantages over existing NMDA antagonists for the treatment of neurolog ical disorders such as stroke and head trauma. Compound 15 is currentl y under clinical evaluation as a neuroprotective agent for stroke.