Prodrugs 2-(Phosphonomethyl)pentanedioic Acid (2-PMPA) as Orally Available Glutamate Carboxypeptidase II Inhibitors

2-(Phosphonomethyl)pentanedioic acid (2-PMPA) is one of the most potent inhibitors of glutamate carboxypeptidase II (GCPII), a zinc metallopeptidase that cleaves glutamate from N-acetylaspartylglutamic acid and folylpoly-γ-glutamate. Due to the presence of multiple acidic groups, 2-PMPA exhibits poor oral bioavailability, limiting its therapeutic utility despite its potent GCPII inhibitory activity. One approach to address this challenge is to develop prodrugs of 2-PMPA with enhanced lipophilicity and improved oral absorption as demonstrated by tris-POC-2-PMPA and tetra-ODOL-2-PMPA. To expand the diversity of our prodrug strategy for 2-PMPA, we explored two promoieties for the phosphonate group of 2-PMPA, ProTide and cycloSal groups, while converting the two carboxylic acids to ester promoieties. The resulting prodrugs were assessed for their ability to deliver 2-PMPA in plasma in mice following oral administration. Among them, several cycloSal-based prodrugs delivered micromolar levels of 2-PMPA in plasma following oral administration, representing another effective prodrug strategy to orally deliver 2-PMPA.