Discovery of Orally Available Prodrugs of the Glutamate Carboxypeptidase II (GCPII) Inhibitor 2-Phosphonomethylpentanedioic Acid (2-PMPA)
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
Grant support
R01 CA161056
NCI NIH HHS - United States
R01CA161056
NCI NIH HHS - United States
- MeSH
- Antigens, Surface MeSH
- Administration, Oral MeSH
- Biological Availability MeSH
- Glutamate Carboxypeptidase II antagonists & inhibitors MeSH
- Protease Inhibitors chemistry pharmacology MeSH
- Microsomes, Liver MeSH
- Humans MeSH
- Mice MeSH
- Neuroprotective Agents chemical synthesis pharmacology MeSH
- Drug Discovery MeSH
- Prodrugs chemical synthesis pharmacology MeSH
- Dogs MeSH
- In Vitro Techniques MeSH
- Structure-Activity Relationship MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Dogs MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
- Names of Substances
- Antigens, Surface MeSH
- FOLH1 protein, human MeSH Browser
- Glutamate Carboxypeptidase II MeSH
- Protease Inhibitors MeSH
- Neuroprotective Agents MeSH
- Prodrugs MeSH
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 α- and γ-carboxylates unsubstituted. This attempt was unsuccessful due to the chemical instability of the bis-POC/POM derivatives. Addition of α,γ-diesters and α-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 α-carboxylate, we synthesized Tris-POC-2-PMPA (21b), which afforded excellent release of 1 following oral administration in both mice and dog.
Department of Chemistry McDaniel College Westminster Maryland 21157 United States
Johns Hopkins Drug Discovery Johns Hopkins University Baltimore Maryland 21205 United States
References provided by Crossref.org
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