Long lasting antinociceptive properties of enkephalin degrading enzyme (NEP and APN) inhibitor prodrugs

被引：36

作者：

Chen, HX ^{[1
]}

Noble, F ^{[1
]}

Roques, BP ^{[1
]}

Fournié-Zaluski, MC ^{[1
]}

机构：

[1] UFR Sci Pharmaceut & Biol, Dept Pharmacochim Mol & Struct, INSERM U266, CNRS UMR 8600, F-75270 Paris 06, France

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2001年 / 44卷 / 21期

关键词：

D O I：

10.1021/jm0102248

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Prodrugs of phosphinic dual inhibitors of the enkephalin degrading enzymes, neutral endopeptidase (NEP) and aminopeptidase N (APN), corresponding to the formula H3N+CH(R-1)P(O)(OR)CH2CH(CH(2)Bip)CONHCH(CH3)COOCH2Ph, with R-1 = CH3 or Ph and R being a benzyl ester, a S-acyl-2-thioethyl derivative, or an acyloxyalkyl group, were synthesized to improve the poor central bioavailability of their precursors. As expected, these compounds (50 mg/kg, iv or ip) induced long lasting (similar to2 h) antinociceptive responses in the hot plate test in mice with a ceiling effect varying between 25 and 42% of analgesia. A very rapid hydrolysis of the carboxylate ester contrasting with a slow deprotection of the phosphinate group (t(1/2) similar to 1 h) was observed in serum while 80% of free drug was obtained after 1 h incubation with brain membranes. These results account for the long duration of action observed with these prodrugs.

引用

页码：3523 / 3530

页数：8

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