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.

Institute of Biotechnology Academy of Sciences of the Czech Republic vvi 166 10 Prague Czech Republic

Institute of Organic Chemistry and Biochemistry Academy of Sciences of the Czech Republic vvi 166 10 Prague Czech Republic

000      

00000naa a2200000 a 4500

001      

bmc18016459

003      

CZ-PrNML

005      

20180515103755.0

007      

ta

008      

180515s2017 xxu f 000 0|eng||

009      

AR

024    7_

$a 10.1021/acs.jmedchem.7b00825 $2 doi

035    __

$a (PubMed)28759215

040    __

$a ABA008 $b cze $d ABA008 $e AACR2

041    0_

$a eng

044    __

$a xxu

100    1_

$a Rais, Rana

245    10

$a Discovery of a para-Acetoxy-benzyl Ester Prodrug of a Hydroxamate-Based Glutamate Carboxypeptidase II Inhibitor as Oral Therapy for Neuropathic Pain / $c R. Rais, J. Vávra, T. Tichý, RP. Dash, AJ. Gadiano, L. Tenora, L. Monincová, C. Bařinka, J. Alt, SC. Zimmermann, CE. Slusher, Y. Wu, K. Wozniak, P. Majer, T. Tsukamoto, BS. Slusher,

520    9_

$a 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.

650    _2

$a aplikace orální $7 D000284

650    _2

$a analgetika $x chemie $x farmakokinetika $x farmakologie $x terapeutické užití $7 D000700

650    _2

$a zvířata $7 D000818

650    _2

$a objevování léků $7 D055808

650    _2

$a inhibitory enzymů $x chemie $x farmakokinetika $x farmakologie $x terapeutické užití $7 D004791

650    _2

$a esterifikace $7 D004951

650    _2

$a glutamátkarboxypeptidasa II $x antagonisté a inhibitory $x metabolismus $7 D043425

650    _2

$a lidé $7 D006801

650    _2

$a kyseliny hydroxamové $x chemie $x farmakokinetika $x farmakologie $x terapeutické užití $7 D006877

650    _2

$a mužské pohlaví $7 D008297

650    _2

$a myši $7 D051379

650    _2

$a neuralgie $x farmakoterapie $x enzymologie $7 D009437

650    _2

$a prekurzory léčiv $x chemie $x farmakokinetika $x farmakologie $x terapeutické užití $7 D011355

650    _2

$a krysa rodu Rattus $7 D051381

650    _2

$a potkani Sprague-Dawley $7 D017207

655    _2

$a časopisecké články $7 D016428

700    1_

$a Vávra, Jan $u Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, vvi , 166 10 Prague, Czech Republic.

700    1_

$a Tichý, Tomáš $u Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, vvi , 166 10 Prague, Czech Republic.

700    1_

$a Dash, Ranjeet P

700    1_

$a Gadiano, Alexandra J

700    1_

$a Tenora, Lukáš $u Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, vvi , 166 10 Prague, Czech Republic.

700    1_

$a Monincová, Lenka $u Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, vvi , 166 10 Prague, Czech Republic.

700    1_

$a Bařinka, Cyril $u Institute of Biotechnology, Academy of Sciences of the Czech Republic, vvi , 166 10 Prague, Czech Republic.

700    1_

$a Alt, Jesse

700    1_

$a Zimmermann, Sarah C

700    1_

$a Slusher, C Ethan

700    1_

$a Wu, Ying

700    1_

$a Wozniak, Krystyna

700    1_

$a Majer, Pavel $u Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, vvi , 166 10 Prague, Czech Republic.

700    1_

$a Tsukamoto, Takashi

700    1_

$a Slusher, Barbara S

773    0_

$w MED00010049 $t Journal of medicinal chemistry $x 1520-4804 $g Roč. 60, č. 18 (2017), s. 7799-7809

856    41

$u https://pubmed.ncbi.nlm.nih.gov/28759215 $y Pubmed

910    __

$a ABA008 $b sig $c sign $y a $z 0

990    __

$a 20180515 $b ABA008

991    __

$a 20180515103928 $b ABA008

999    __

$a ok $b bmc $g 1300083 $s 1013299

BAS    __

$a 3

BAS    __

$a PreBMC

BMC    __

$a 2017 $b 60 $c 18 $d 7799-7809 $e 20170918 $i 1520-4804 $m Journal of medicinal chemistry $n J Med Chem $x MED00010049

LZP    __

$a Pubmed-20180515