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

…, Y Ducharme, JA Yergey, DA Nicoll-Griffith

Index: Chauret, Nathalie; Guay, Daniel; Li, Chun; Day, Stephen; Silva, Jose; Blouin, Marc; Ducharme, Yves; Yergey, James A.; Nicoll-Griffith, Deborah A. Bioorganic and Medicinal Chemistry Letters, 2002 , vol. 12, # 16 p. 2149 - 2152

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Citation Number: 29

Abstract

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 ...