Number of the records: 1

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

SYSNO ASEP	0459240
Document Type	J - Journal Article
R&D Document Type	Journal Article
Subsidiary J	Článek ve WOS
Title	Discovery of Orally Available Prodrugs of the Glutamate Carboxypeptidase II (GCPII) Inhibitor 2-Phosphonomethylpentanedioic Acid (2-PMPA)
Author(s)	Majer, Pavel (UOCHB-X) Jančařík, Andrej (UOCHB-X)_{ORCID, RID} Krečmerová, Marcela (UOCHB-X)_{RID, ORCID} Tichý, Tomáš (UOCHB-X)_RID Tenora, Lukáš (UOCHB-X)_ORCID Wozniak, K. (US) Wu, Y. (US) Pommier, E. (US) Ferraris, D. (US) Rais, R. (US) Slusher, B. S. (US)
Source Title	Journal of Medicinal Chemistry. - : American Chemical Society - ISSN 0022-2623 Roč. 59, č. 6 (2016), s. 2810-2819
Number of pages	10 s.
Language	eng - English
Country	US - United States
Keywords	glutamate carboxypeptidase II ; glutamate ; 2-PMPA ; prodrug
Subject RIV	CC - Organic Chemistry
Institutional support	UOCHB-X - RVO:61388963
UT WOS	000372946500037
EID SCOPUS	84962173335
DOI	10.1021/acs.jmedchem.6b00062
Annotation	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.
Workplace	Institute of Organic Chemistry and Biochemistry
Contact	asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Viktorie Chládková, Tel.: 232 002 434
Year of Publishing	2017

Number of the records: 1