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. Replacement of the methoxy and cyclopentyloxy substituents on the catechol moiety of PDE4 inhibitors resulted in the discovery of potential drug candidates where the formation of reactive metabolites that could covalently bind to microsomal proteins was significantly reduced or eliminated.