Isoxazole analogues bind the System [formula omitted] transporter: Structure–activity relationship and pharmacophore model

Abstract

Analogues of amino methylisoxazole propionic acid (AMPA), were prepared from a common intermediate 12, including lipophilic analogues using lateral metalation and electrophilic quenching, and were evaluated at System x c - . Both the 5-naphthylethyl-( 16) and 5-naphthylmethoxymethyl-( 17) analogues adopt an E-conformation in the solid state, yet while the former has robust binding at System x c - , the latter is virtually devoid of activity. The most potent analogues were amino acid naphthyl-ACPA 7g, and hydrazone carboxylic acid, 11e Y = Y′ = 3,5-(CF 3) 2, which both inhibited glutamate uptake by the System x c - transporter with comparable potency to the endogenous substrate cystine, whereas in contrast the closed isoxazolo[3,4- d] pyridazinones 13 have significantly lower activity. A preliminary pharmacophore model has been constructed to provide insight into the analogue structure–activity relationships.