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.

• MeSH
• analgetika chemie   farmakokinetika   farmakologie   terapeutické užití   MeSH
• aplikace orální MeSH
• esterifikace MeSH
• glutamátkarboxypeptidasa II antagonisté a inhibitory   metabolismus   MeSH
• inhibitory enzymů chemie   farmakokinetika   farmakologie   terapeutické užití   MeSH
• krysa rodu rattus MeSH
• kyseliny hydroxamové chemie   farmakokinetika   farmakologie   terapeutické užití   MeSH
• lidé MeSH
• myši MeSH
• neuralgie farmakoterapie   enzymologie   MeSH
• objevování léků MeSH
• potkani Sprague-Dawley MeSH
• prekurzory léčiv chemie   farmakokinetika   farmakologie   terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

• MeSH
• buňky zadních rohů míšních enzymologie   MeSH
• krysa rodu rattus MeSH
• nemoci periferního nervového systému enzymologie   patologie   MeSH
• neuralgie enzymologie   MeSH
• oxid dusnatý biosyntéza   MeSH
• spinální ganglia enzymologie   MeSH
• synthasa oxidu dusnatého metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH