Number of the records: 1
Discovery of a para-Acetoxy-benzyl Ester Prodrug of a Hydroxamate-Based Glutamate Carboxypeptidase II Inhibitor as Oral Therapy for Neuropathic Pain
- 1.
SYSNO ASEP 0480326 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Discovery of a para-Acetoxy-benzyl Ester Prodrug of a Hydroxamate-Based Glutamate Carboxypeptidase II Inhibitor as Oral Therapy for Neuropathic Pain Author(s) Rais, R. (US)
Vávra, Jan (UOCHB-X) RID
Tichý, Tomáš (UOCHB-X) RID
Dash, R. P. (US)
Gadiano, A. J. (US)
Tenora, Lukáš (UOCHB-X) ORCID
Monincová, Lenka (UOCHB-X)
Bařinka, Cyril (BTO-N) RID, ORCID
Alt, J. (US)
Zimmermann, S. C. (US)
Slusher, C. E. (US)
Wu, Y. (US)
Wozniak, K. (US)
Majer, Pavel (UOCHB-X)
Tsukamoto, T. (US)
Slusher, B. S. (US)Source Title Journal of Medicinal Chemistry. - : American Chemical Society - ISSN 0022-2623
Roč. 60, č. 18 (2017), s. 7799-7809Number of pages 11 s. Language eng - English Country US - United States Keywords linked acidic dipeptidase ; peripheral mononeuropathy ; biological activity Subject RIV CC - Organic Chemistry OECD category Organic chemistry Subject RIV - cooperation Institute of Biotechnology - Organic Chemistry R&D Projects LM2015043 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) ED1.1.00/02.0109 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Institutional support UOCHB-X - RVO:61388963 ; BTO-N - RVO:86652036 UT WOS 000412150300010 EID SCOPUS 85030255944 DOI 10.1021/acs.jmedchem.7b00825 Annotation 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. Workplace Institute of Organic Chemistry and Biochemistry Contact asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Jana Procházková, Tel.: 220 183 418 Year of Publishing 2018
Number of the records: 1