Therapeutic potential of phosphodiesterase 4 inhibitors in allergic diseases.

Abstract

Cyclic adenosine monophosphate (cAMP) is thought to be associated with inflammatory cell activity: high levels tend to decrease proliferation and cytokine secretion, whereas low concentrations have the opposite effect (1). Since many phosphodiesterases (PDEs) degrade cAMP, inhibitors of this enzyme decrease inflammatory cell activity. Theophylline, which has nonselective PDE inhibitor activity in addition to its other mechanisms of action, has been used in the treatment of asthma for many years. Unfortunately, because of the important role of PDEs in the cell, nonspecific inhibition of these enzymes causes many undesirable side effects. The discovery of PDE isoenzyme families (PDE1-PDE10), their subtypes (HPDE4 and LPDE4) and their differential distribution among the cell types, as well as their specific functions in controlling cell processes, has led to the development of new, specific PDE4 inhibitors. This review details the rationale for the use of PDE4 inhibitors in the treatment of allergic disease. In addition, the effects of PDE4 inhibitors in vitro, in preclinical animal models and in the clinic are covered. Finally, up-to-date information on the most recently developed inhibitors, such as SB-207499, CDP-840, AWD-12-281 and D-4418, is provided.