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

Rana Rais, Jan Vávra, Tomáš Tichý, Ranjeet P. Dash, Alexandra J. Gadiano, Lukáš Tenora, Lenka Monincová, Cyril Bařinka, Jesse Alt, Sarah C. Zimmermann, C. Ethan Slusher, Ying Wu, Krystyna Wozniak, Pavel Majer, Takashi Tsukamoto, Barbara S. Slusher

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)7799-7809
Number of pages11
JournalJournal of medicinal chemistry
Volume60
Issue number18
DOIs
StatePublished - Sep 28 2017

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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