2-(phosphonomethyl)pentanedioic acid

**2-(phosphonomethyl)pentanedioic acid (2-PMPA)** is a potent, selective small molecule inhibitor of the enzyme **glutamate carboxypeptidase II (GCPII)**, also known as **NAALADase** or **prostate-specific membrane antigen (PSMA)**[1][3][6][9]. It exhibits subnanomolar inhibitory potency (IC50 ~300 pM, Ki ~280 pM) for GCPII. Through inhibition of GCPII, 2-PMPA increases levels of the neuroprotective dipeptide NAAG and attenuates glutamate elevations associated with neurological injury and excitotoxicity[1][3][6]. 2-PMPA has demonstrated efficacy in preclinical models of **neurological and psychiatric diseases** (including stroke and drug addiction), and has also been investigated in models of **inflammatory bowel disease** and **cancer**[1][3][5]. However, its clinical development has been limited by **very poor oral bioavailability** and poor brain penetration due to its highly acidic nature[1][3]. Multiple prodrug strategies and alternative routes of administration (such as intranasal delivery) have been investigated to improve pharmacokinetics[1][3]. Not approved for human therapeutic use as of July 2025.

Other names

2-(phosphonomethyl)pentanedioic acid2-PMPA cpdDTXSID90436036DTXSID-90436036DTXSID 90436036DTXCID10386862DTXCID-10386862DTXCID 10386862