Dual PDE3/4 and PDE4 Inhibitors: Novel Treatments For COPD and Other Inflammatory Airway Diseases

Abstract

Selective phosphodiesterase (PDE) 4 and dual PDE3/4 inhibitors have attracted considerable interest as potential therapeutic agents for the treatment of respiratory diseases, largely by virtue of their anti-inflammatory (PDE4) and bifunctional bronchodilator/anti-inflammatory (PDE3/4) 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 PDE4 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 PDE3 (A,B) or PDE4 (A,B,C,D) subtypes. Developing an inhaled dual PDE3/4 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 PDE3 or PDE4 alone, given the potential positive interactions with regard to anti-inflammatory and bronchodilator effects that have been observed pre-clinically with dual inhibition of PDE3 and PDE4 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.

Roflumilast N-Oxide in Combination with Formoterol Enhances the Antiinflammatory Effect of Dexamethasone in Airway Smooth Muscle Cells

“…In particular, the PDE4 isoform is known to inactivate the major bronchodilatory second messenger, cyclic adenosine monophosphate (cAMP) and together with β2-agonists, PDE4 inhibitors can increase the amount of intracellular cAMP in airway smooth muscle (ASM) and reverse bronchospasm. However, there has been an emerging appreciation of the anti-inflammatory effects of these medicines (2,3) that can also occur in a cAMP dependent manner (4). Utilizing primary cultures of airway smooth muscle (ASM) cells, we recently examined the ability of panel of PDE4 inhibitors to enhance cAMP production in response to the long acting β2-agonist (LABA) formoterol (5).…”

Superiority of Combined Phosphodiesterase PDE3/PDE4 Inhibition over PDE4 Inhibition Alone on Glucocorticoid- and Long-Acting β2-Adrenoceptor Agonist–Induced Gene Expression in Human Airway Epithelial Cells

“…Although improvements in lung function may occur in the absence of ICSs (Calverley et al, 2009), the additional benefit of adding roflumilast for patients already taking ICSs fits with the fact that PDE4 inhibitors, like LABAs, also enhance glucocorticoid-dependent transcription (Miller et al, 2002;Kaur et al, 2008;Rennard et al, 2011;Moodley et al, 2013;Giembycz and Newton, 2014). Since PDE3 inhibitors are bronchodilators in humans and may also have anti-inflammatory activity (Franciosi et al, 2013), combined PDE3/PDE4 inhibition may provide a superior treatment option compared with a PDE4 inhibitor alone Abbott-Banner and Page, 2014). In this study, we used human bronchial epithelial cells, which express PDE3 and PDE4 (Rabe et al, 1993;Dent et al, 1998;Wright et al, 1998) and respond to LABAs and glucocorticoids , as a model system to test this hypothesis using antiinflammatory gene expression that is induced by LABAs and glucocorticoids as a functionally relevant output.…”

Long-acting bronchodilators in COPD: where are we now and where are we going?

“…There is documentation that the PDE3 isoenzyme predominates in airway smooth muscle and inhibition of this enzyme, rather than PDE4, leads to airway smooth muscle relaxation, whereas the PDE4 isoenzyme is the predominant isoenzyme in the majority of inflammatory cells, including neutrophils [70]. Consequently, dual PDE3/PDE4 inhibitors can combine bronchodilation with anti-inflammatory activity, representing a potential new class of drugs for the treatment of patients with asthma or COPD [70].…”