Počet záznamů: 1
Discovery of a para-Acetoxy-benzyl Ester Prodrug of a Hydroxamate-Based Glutamate Carboxypeptidase II Inhibitor as Oral Therapy for Neuropathic Pain
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SYSNO ASEP 0480326 Druh ASEP J - Článek v odborném periodiku Zařazení RIV J - Článek v odborném periodiku Poddruh J Článek ve WOS Název Discovery of a para-Acetoxy-benzyl Ester Prodrug of a Hydroxamate-Based Glutamate Carboxypeptidase II Inhibitor as Oral Therapy for Neuropathic Pain Tvůrce(i) 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)Zdroj.dok. Journal of Medicinal Chemistry. - : American Chemical Society - ISSN 0022-2623
Roč. 60, č. 18 (2017), s. 7799-7809Poč.str. 11 s. Jazyk dok. eng - angličtina Země vyd. US - Spojené státy americké Klíč. slova linked acidic dipeptidase ; peripheral mononeuropathy ; biological activity Vědní obor RIV CC - Organická chemie Obor OECD Organic chemistry Vědní obor RIV – spolupráce Biotechnologický ústav - Organická chemie CEP LM2015043 GA MŠMT - Ministerstvo školství, mládeže a tělovýchovy ED1.1.00/02.0109 GA MŠMT - Ministerstvo školství, mládeže a tělovýchovy Institucionální podpora UOCHB-X - RVO:61388963 ; BTO-N - RVO:86652036 UT WOS 000412150300010 EID SCOPUS 85030255944 DOI 10.1021/acs.jmedchem.7b00825 Anotace 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. Pracoviště Ústav organické chemie a biochemie Kontakt asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Viktorie Chládková, Tel.: 232 002 434 Rok sběru 2018
Počet záznamů: 1