Discovery of Orally Available Prodrugs of the Glutamate Carboxypeptidase II (GCPII) Inhibitor 2-Phosphonomethylpentanedioic Acid (2-PMPA)

0459240 - ÚOCHB 2017 RIV US eng J - Journal Article
Majer, Pavel - Jančařík, Andrej - Krečmerová, Marcela - Tichý, Tomáš - Tenora, Lukáš - Wozniak, K. - Wu, Y. - Pommier, E. - Ferraris, D. - Rais, R. - Slusher, B. S.
Discovery of Orally Available Prodrugs of the Glutamate Carboxypeptidase II (GCPII) Inhibitor 2-Phosphonomethylpentanedioic Acid (2-PMPA).
Journal of Medicinal Chemistry. Roč. 59, č. 6 (2016), s. 2810-2819. ISSN 0022-2623. E-ISSN 1520-4804
Institutional support: RVO:61388963
Keywords : glutamate carboxypeptidase II * glutamate * 2-PMPA * prodrug
Subject RIV: CC - Organic Chemistry
Impact factor: 6.259, year: 2016

2-Phosphonomethylpentanedioic acid (1, 2-PMPA) is a potent inhibitor of glutamate carboxypeptidase II which has demonstrated robust neuroprotective efficacy in many neurological disease models. However, 1 is highly polar containing a phosphonate and two carboxylates, severely limiting its oral bioavailability. We strategized to mask the polar groups via a prodrug approach, increasing the likelihood of passive oral absorption. Our initial strategy was to cover the phosphonate with hydrophobic moieties such as pivaloyloxymethyl (POM) and isopropyloxycarbonyloxymethyl (POC) while keeping the alpha- and gamma-carboxylates unsubstituted. This attempt was unsuccessful due to the chemical instability of the bis-POC/POM derivatives. Addition of alpha,gamma-diesters and alpha-monoesters enhanced chemical stability and provided excellent oral exposure in mice, but these mixed esters were too stable in vivo, resulting in minimal release of 1. By introducing POC groups on both the phosphonate and a-carboxylate, we synthesized Tris-POC-2-PMPA (21b), which afforded excellent release of 1 following oral administration in both mice and dog.
Permanent Link: http://hdl.handle.net/11104/0259472