Evidence map›Paper›PMID 40881187›Full record

ArticleACS medicinal chemistry letters2025

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

Niyada Hin, Chae Bin Lee, Sadakatali Gori, Barbara S Slusher, Rana Rais, Takashi Tsukamoto

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in ACS medicinal chemistry letters, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

6 authors.

Niyada HinJohns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Chae Bin LeeJohns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.ORCID 0000-0003-4551-9191
Sadakatali GoriJohns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.ORCID 0000-0003-0840-829X
Barbara S SlusherJohns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.ORCID 0000-0001-9814-4157
Rana RaisJohns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.ORCID 0000-0003-4059-2453
Takashi TsukamotoJohns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.ORCID 0000-0002-0216-7520

Funding

Development of GCPII inhibitors for the treatment of age-related cognitive disordersR01AG068130 · NIA · JOHNS HOPKINS UNIVERSITY · PI ARNSTEN, AMY F.T., SLUSHER, BARBARA STAUCH · 2020 to 2024
$3.8M
Acquisition of a 500 MHz NMR Spectrometer to Support Small-Molecule Chemistry at Johns Hopkins Medical SchoolS10OD034217 · OD · JOHNS HOPKINS UNIVERSITY · PI BHAT, SHRIDHAR · 2024 to 2024
$425k
NIA NIH HHS R01 AG068130NIH HHS S10 OD034217
6 · The paper itself

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.

Indexed as

2-(phosphonomethyl)pentanedioic acid (2-PMPA)cycloSalglutamate carboxypeptidase II (GCPII) prodrugsProTide

Identifiers

PMID40881187
PMCPMC12385607

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.