Pharmacology of phosphodiesterase inhibitors
Cyclic 3′, 5′ adenosine monophosphate (cAMP) is pivotal in modulating physiological responses and elevation of this ubiquitous second messenger has been demonstrated to be broadly anti-inflammatory. Phosphodiesterases (PDE), hydrolyse the catalytic breakdown of both cAMP and cyclic 3′, 5′ guanosine monophosphate (cGMP), to their inactive mononucleotides, 5′-AMP and 5′-GMP which are unable to activate cyclic nucleotidedependent protein kinase cascades. Consequently, they play a vital role in regulating intracellular levels of cyclic nucleotides. Advances in molecular pharmacology have identified 11 PDE families and the success of sidenafil, a PDE5 selective inhibitor, in treating erectile dysfunction has invigorated research into the therapeutic potential of selective PDE inhibitors in other diseases. Non-selective PDE inhibitors such as theophylline have been in use since the 1950s for the treatment of inflammatory airways diseases, although use has been limited due to their narrow therapeutic index and sideeffect profile. As a result, there have been attempts to improve the therapeutic window and the PDE4 isoenzyme, expressed in the majority of leukocytes, has been identified as an important target in the treatment of asthma and COPD and a number of inhibitors, which are at least 30-fold selective for PDE4, are undergoing clinical development and are discussed later in this chapter. This part of the chapter will discuss the role of PDEs in modulating inflammation, with particular reference to COPD and highlight how our increasing understanding of the molecular biology of PDE4 is assisting in the development of potent, new drugs.