Phosphodiesterase 4 inhibitors and the treatment of asthma: where are we now and where do we go from here?

Abstract

Research conducted over the last 20 years has established that inflammation of the airways is central to the airway dysfunction that characterises asthma. Typically, the airway wall is infiltrated by a variety of cells including mast cells, eosinophils and T lymphocytes, which have deviated towards a T(H)2 phenotype. Together, these cells release a plethora of mediators including interleukin (IL)-4, IL-5, granulocyte/macrophage colony-stimulating factor and eotaxin which ultimately cause the histopathology and symptoms of asthma. Glucocorticosteroids are the only drugs currently available that effectively impact upon this inflammation and resolve, to a greater or lesser extent, compromised lung function. However, steroids are nonselective and generally unsuitable for paediatric use. New drugs are clearly required. One group of potential therapeutic agents for asthma are inhibitors of cyclic AMP-specific phosphodiesterase (PDE), of which theophylline may be considered a prototype. It is now known that PDE is a generic term which refers to at least 11 distinct enzyme families that hydrolyse cAMP and/or cGMP. Over the last decade, inhibitors of PDE4 (a cAMP-specific family that negatively regulates the function of almost all pro-inflammatory and immune cells, and exerts widespread anti-inflammatory activity in animal models of asthma) have been developed with the view to reducing the adverse effects profile associated with non-selective inhibitors such as theophylline. Such is the optimism regarding PDE4 as a viable therapeutic target that more than 100 PDE4 inhibitor patent applications have been filed since 1996 by 13 major pharmaceutical companies. This article reviews the progress of PDE4 inhibitors as anti-inflammatory agents, and identifies problems that have been encountered by the pharmaceutical industry in the clinical development of these drugs and what strategies are being considered to overcome them.