Phosphodiesterase Inhibitors in the Treatment of Inflammatory Diseases

Abstract

Phosphodiesterase 4 (PDE4) belongs to a family of enzymes which catalyzes the breakdown of 3, 5'-adenosine cyclic monophosphate (cAMP) and is ubiquitously expressed in inflammatory cells. There is little evidence that inflammatory diseases are caused by increased expression of this isoenzyme, although human inflammatory cell activity can be suppressed by selective PDE4 inhibitors. Consequently, there is intense interest in the development of selective PDE4 inhibitors for the treatment of a range of inflammatory diseases, including asthma, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease, and psoriasis. Recent clinical trials with roflumilast in COPD have confirmed the therapeutic potential of targeting PDE4 and recently roflumilast has been approved for marketing in Europe and the USA, although side effects such as gastrointestinal disturbances, particularly nausea and emesis as well as headache and weight loss, may limit the use of this drug class, at least when administered by the oral route. However, a number of strategies are currently being pursued in attempts to improve clinical efficacy and reduce side effects of PDE4 inhibitors, including delivery via the inhaled route, development of nonemetic PDE4 inhibitors, mixed PDE inhibitors, and/or antisense biologicals targeted toward PDE4.