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

  • ACS Med Chem Lett. 2025 Aug 19:10.1021/acsmedchemlett.5c00384. doi: 10.1021/acsmedchemlett.5c00384.
Niyada Hin  1  2 ,  Chae Bin Lee  1  2 ,  Sadakatali Gori  1  2 ,  Barbara S Slusher  1  2 ,  Rana Rais  1  2 ,  Takashi Tsukamoto  1  2
Affiliations
  • 1. Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 2. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
PMID: 40881187 DOI: 10.1021/acsmedchemlett.5c00384
Abstract

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.

Keywords
2-(phosphonomethyl)pentanedioic acid (2-PMPA); ProTide; cycloSal; glutamate carboxypeptidase II (GCPII) prodrugs.
Products