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Discovery of a para-Acetoxy-benzyl Ester Prodrug of a Hydroxamate-Based Glutamate Carboxypeptidase II Inhibitor as Oral Therapy for Neuropathic Pain

The result's identifiers

  • Result code in IS VaVaI

    <a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F17%3A00480326" target="_blank" >RIV/61388963:_____/17:00480326 - isvavai.cz</a>

  • Alternative codes found

    RIV/86652036:_____/17:00480326

  • Result on the web

    <a href="http://dx.doi.org/10.1021/acs.jmedchem.7b00825" target="_blank" >http://dx.doi.org/10.1021/acs.jmedchem.7b00825</a>

  • DOI - Digital Object Identifier

    <a href="http://dx.doi.org/10.1021/acs.jmedchem.7b00825" target="_blank" >10.1021/acs.jmedchem.7b00825</a>

Alternative languages

  • Result language

    angličtina

  • Original language name

    Discovery of a para-Acetoxy-benzyl Ester Prodrug of a Hydroxamate-Based Glutamate Carboxypeptidase II Inhibitor as Oral Therapy for Neuropathic Pain

  • Original language description

    4-Carboxy-alpha-[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.

  • Czech name

  • Czech description

Classification

  • Type

    J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database

  • CEP classification

  • OECD FORD branch

    10401 - Organic chemistry

Result continuities

  • Project

    Result was created during the realization of more than one project. More information in the Projects tab.

  • Continuities

    I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Others

  • Publication year

    2017

  • Confidentiality

    S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Data specific for result type

  • Name of the periodical

    Journal of Medicinal Chemistry

  • ISSN

    0022-2623

  • e-ISSN

  • Volume of the periodical

    60

  • Issue of the periodical within the volume

    18

  • Country of publishing house

    US - UNITED STATES

  • Number of pages

    11

  • Pages from-to

    7799-7809

  • UT code for WoS article

    000412150300010

  • EID of the result in the Scopus database

    2-s2.0-85030255944