Phosphodiesterase inhibitors for the treatment of asthma and chronic obstructive pulmonary disease

Xanthines like theophylline have long been recognised as being effective drugs for the treatment of asthma and chronic obstructive pulmonary disease (COPD). They are of interest as they possess both anti-inflammatory and bronchodilator activity in the same molecule. Since the discovery of phosphodiesterases (PDEs) in the late 1950s, it has been suggested that xanthines work, in part, by acting as non-selective PDE inhibitors. However, it has also been suggested that the ability of xanthines to non-selectively inhibit PDEs contributes to their many unwanted side effects, thus limiting their use since the arrival of inhaled drugs with more favourable safety profiles. As our understanding of PDEs has improved over the last 30 years, and with the recognition that the distribution of different PDEs varies across different cell types, this family of enzymes has been widely investigated as targets for novel drugs. In particular, PDE3 in airway smooth muscle and PDE4 and PDE7 in inflammatory cells have been targeted to provide new bronchodilators and anti-inflammatory agents, respectively. This review discusses the progress made in this field over the last decade in the development of selective PDE inhibitors to treat COPD and asthma.