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

0480326 - ÚOCHB 2018 RIV US eng J - Článek v odborném periodiku
Rais, R. - Vávra, Jan - Tichý, Tomáš - Dash, R. P. - Gadiano, A. J. - Tenora, Lukáš - Monincová, Lenka - Bařinka, Cyril - Alt, J. - Zimmermann, S. C. - Slusher, C. E. - Wu, Y. - Wozniak, K. - Majer, Pavel - Tsukamoto, T. - Slusher, B. S.
Discovery of a para-Acetoxy-benzyl Ester Prodrug of a Hydroxamate-Based Glutamate Carboxypeptidase II Inhibitor as Oral Therapy for Neuropathic Pain.
Journal of Medicinal Chemistry. Roč. 60, č. 18 (2017), s. 7799-7809. ISSN 0022-2623. E-ISSN 1520-4804
Grant CEP: GA MŠMT(CZ) LM2015043; GA MŠMT(CZ) ED1.1.00/02.0109
Institucionální podpora: RVO:61388963 ; RVO:86652036
Klíčová slova: linked acidic dipeptidase * peripheral mononeuropathy * biological activity
Obor OECD: Organic chemistry; Organic chemistry (BTO-N)
Impakt faktor: 6.253, rok: 2017

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.
Trvalý link: http://hdl.handle.net/11104/0276130