TY - JOUR
T1 - Discovery of a para-Acetoxy-benzyl Ester Prodrug of a Hydroxamate-Based Glutamate Carboxypeptidase II Inhibitor as Oral Therapy for Neuropathic Pain
AU - Rais, Rana
AU - Vávra, Jan
AU - Tichý, Tomáš
AU - Dash, Ranjeet P.
AU - Gadiano, Alexandra J.
AU - Tenora, Lukáš
AU - Monincová, Lenka
AU - Bařinka, Cyril
AU - Alt, Jesse
AU - Zimmermann, Sarah C.
AU - Slusher, C. Ethan
AU - Wu, Ying
AU - Wozniak, Krystyna
AU - Majer, Pavel
AU - Tsukamoto, Takashi
AU - Slusher, Barbara S.
N1 - Funding Information:
This research was supported by NIH grant RO1CA161056 (to B.S.S.) and the Institute of Organic Chemistry and Biochemistry of the Academy of Sciences of the Czech Republic, vvi (RVO 61388963), and in part supported by the CAS (RVO: 86652036), MEYS CR (LM2015043 CIISB), and project BIOCEV (CZ.1.05/1.1.00/02.0109) from the ERDF to C.B.
Publisher Copyright:
© 2017 American Chemical Society.
PY - 2017/9/28
Y1 - 2017/9/28
N2 - 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.
AB - 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.
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U2 - 10.1021/acs.jmedchem.7b00825
DO - 10.1021/acs.jmedchem.7b00825
M3 - Article
C2 - 28759215
AN - SCOPUS:85030255944
SN - 0022-2623
VL - 60
SP - 7799
EP - 7809
JO - Journal of medicinal chemistry
JF - Journal of medicinal chemistry
IS - 18
ER -