Improving Metabolic Stability of Phosphodiesterase-4 Inhibitors Containing a Substituted Catechol: Prevention of Reactive Intermediate Formation and Covalent Binding.

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.