ArticleJournal of medicinal chemistry2017
Discovery of a para-Acetoxy-benzyl Ester Prodrug of a Hydroxamate-Based Glutamate Carboxypeptidase II Inhibitor as Oral Therapy for Neuropathic Pain.
Article in Journal of medicinal chemistry, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
What it found
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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.
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.
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Who cites it
9 citing papers in PubMed, 31 citations in OpenAlex.
- Development of Styryl-Modified 3,4-Dihydropyrimidin-2(1H)-ones as Potential Antitumor Agents.ChemMedChem · 2026Article
- Unsaturated Phosphorus Electrophiles to Probe Protein Tyrosine Phosphatases.Angewandte Chemie (International ed. in English) · 2026Article
- Inhibition of brain glutamate carboxypeptidase II (GCPII) to enhance cognitive function.Advances in pharmacology (San Diego, Calif.) · 2025Review
- Structural, Biochemical, and Computational Characterization of Sulfamides as Bimetallic Peptidase Inhibitors.Journal of chemical information and modeling · 2024Article
- Combination ofJournal of chemical information and modeling · 2023Article
- D-DOPA Is a Potent, Orally Bioavailable, Allosteric Inhibitor of Glutamate Carboxypeptidase II.Pharmaceutics · 2022Article
- Novel Analgesics with Peripheral Targets.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2020Review
- OleD Loki as a Catalyst for Hydroxamate Glycosylation.Chembiochem : a European journal of chemical biology · 2020Article
- Enhanced Oral Bioavailability of 2-(Phosphonomethyl)-pentanedioic Acid (2-PMPA) from its (5-Methyl-2-oxo-1,3-dioxol-4-yl)methyl (ODOL)-Based Prodrugs.Molecular pharmaceutics · 2019Article
Corrections and comments
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Authors and funding
16 authors at 2 institutions in 1 country.
Funding
Abstract
4-Carboxy-α-[3-(hydroxyamino)-3-oxopropyl]-benzenepropanoic acid 1 is a potent hydroxamate-based inhibitor of glutamate carboxypeptidase II. In an attempt to improve its poor oral pharmacokinetics, we synthesized a series of prodrugs by masking its hydrophilic hydroxamate group. Prodrugs were evaluated for oral availability in mice and showed varying degree of plasma exposure to 1. Of these, para-acetoxybenzyl-based, 4-(5-(((4-acetoxybenzyl)oxy)amino)-2-carboxy-5-oxopentyl)benzoic acid, 12, provided 5-fold higher plasma levels of 1 compared to oral administration of 1 itself. Subsequently, para-acetoxybenzyl-based prodrugs with additional ester promoiety(ies) on carboxylate(s) were examined for their ability to deliver 1 to plasma. Isopropyloxycarbonyloxymethyl (POC) ester 30 was the only prodrug that achieved substantial plasma levels of 1. In vitro metabolite identification studies confirmed stability of the ethyl ester of benzoate while the POC group was rapidly hydrolyzed. At oral daily dose-equivalent of 3 mg/kg, 12 exhibited analgesic efficacy comparable to dose of 10 mg/kg of 1 in the rat chronic constrictive injury model of neuropathic pain.
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Registered trials
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.