Design, synthesis and pharmacological activity of novel enantiomerically pure phosphonic acid-based NAALADase inhibitors

Inhibitors of NAALADase have shown promise for a variety of diseases associated with glutamate excitotoxicity, and could be useful for the diagnosis and therapy of prostate cancer. A series of novel enantiomerically pure 2-(phosphonomethyl)pentanedioic acid (2-PMPA) based NAALADase inhibitors were synthesized. These compounds were prepared from previously reported (S)-2-(hydroxyphosphinoylmethyl)pentanedioic acid benzyl ester . Biological test results showed that the new compounds are good to outstanding NAALADase inhibitors. Compounds and showed activity similar to the known potent inhibitor (S)-2-PMPA. Fluorescently labeled inhibitor may potentially be used to study binding to prostate cancer cells by fluorescence microscopy, and siderophore-containing inhibitor may be useful for detection of prostate-derived cancer cells by magnetic resonance imaging (MRI).