Improving metabolic stability of phosphodiesterase-4 inhibitors containing a substituted catechol: Prevention of reactive intermediate formation and covalent binding

被引：55

作者：

Chauret, N ^{[1
]}

Guay, D ^{[1
]}

Li, C ^{[1
]}

Day, S ^{[1
]}

Silva, J ^{[1
]}

Blouin, M ^{[1
]}

Ducharme, Y ^{[1
]}

Yergey, JA ^{[1
]}

Nicoll-Griffith, DA ^{[1
]}

机构：

[1] Merck Frosst Ctr Therapeut Res, Pointe Claire, PQ H9R 4P8, Canada

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2002年 / 12卷 / 16期

关键词：

D O I：

10.1016/S0960-894X(02)00349-9

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A detailed study directed towards metabolic stability optimization of the alkoxy substituents on the catechol moiety of CDP-840 is reported. Replacement of the methoxy and cyclopentyloxy substituents by cyclobutyloxy and/or difluromethoxy groups resulted in the discovery of potent and selective PDE4 inhibitors where the formation of reactive metabolites that could covalently bind to microsomal protein was significantly reduced or eliminated. (C) 2002 Elsevier Science Ltd. All rights reserved.

引用

页码：2149 / 2152

页数：4

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