Chapter 19. Isozyme-Selective Phosphodiesterase Inhibitors as Antiasthmatic Agents

Abstract

Considerable interest has been generated in the potential utility of isozymeselective inhibitors of cyclic nucleotide phosphodiesterase (PDE) inhibitors in the treatment of asthma and other inflammatory disorders. The scientific foundation for the interest is based upon two fundamental principles. First, the inhibition of PDE activity increases the cellular content of two key second messengers, cyclic AMP (CAMP) and cyclic GMP (cGMP), thereby activating specific protein phosphorylation cascades that elicit a variety of functional responses. Increases in cAMP content suppress a broad array of functions in the inflammatory and immune cells. Moreover, both cAMP and cGMP mediate bronchodilation. While these activities are attractive from a therapeutic standpoint, the ubiquitous distribution of cyclic nucleotides and PDEs makes the side effect profile of standard, nonselective PDE inhibitors, unacceptable. This raises the second scientific principle, underpinning the interest in selective PDE inhibitors, as anti-asthmatic and anti-inflammatory agents. Specifically, it is now recognized that several distinct families of PDE isozymes exist with different tissue distributions and functional roles. Consequently, the side effect profile of PDE inhibitors may be improved, by targeting a new generation of compounds, to a specific isozyme that predominates in inflammatory cells and airway smooth muscle.