Dual PDE 3/4 and PDE 4 Inhibitors: Novel Treatments For COPD and Other Inflammatory Airway Diseases

Abstract Selective phosphodiesterase ( PDE ) 4 and dual PDE 3/4 inhibitors have attracted considerable interest as potential therapeutic agents for the treatment of respiratory diseases, largely by virtue of their anti‐inflammatory ( PDE 4) and bifunctional bronchodilator/anti‐inflammatory ( PDE 3/4) effects. Many of these agents have, however, failed in early development for various reasons, including dose‐limiting side effects when administered orally and lack of sufficient activity when inhaled. Indeed, only one selective PDE 4 inhibitor, the orally active roflumilast‐n‐oxide, has to date received marketing authorization. The majority of the compounds that have failed were, however, orally administered and non‐selective for either PDE 3 (A,B) or PDE 4 (A,B,C,D) subtypes. Developing an inhaled dual PDE 3/4 inhibitor that is rapidly cleared from the systemic circulation, potentially with subtype specificity, may represent one strategy to improve the therapeutic index and also exhibit enhanced efficacy versus inhibition of either PDE 3 or PDE 4 alone, given the potential positive interactions with regard to anti‐inflammatory and bronchodilator effects that have been observed pre‐clinically with dual inhibition of PDE 3 and PDE 4 compared with inhibition of either isozyme alone. This MiniReview will summarize recent clinical data obtained with PDE inhibitors and the potential for these drugs to treat COPD and other inflammatory airways diseases such as asthma and cystic fibrosis.