Harnessing the Clinical Efficacy of Phosphodiesterase 4 Inhibitors in Inflammatory Lung Diseases: Dual-Selective Phosphodiesterase Inhibitors and Novel Combination Therapies

Abstract

Phosphodiesterase (PDE) 4 inhibitors have been in development as a novel anti-inflammatory therapy for more than 20 years, with asthma and chronic obstructive pulmonary disease (COPD) being primary indications. Despite initial optimism, only one selective PDE4 inhibitor, roflumilast (Daxas (®)), has been approved for use in humans and available in Canada and the European Union in 2011 for the treatment of a specific population of patients with severe COPD. In many other cases, the development of PDE4 inhibitors of various structural classes has been discontinued due to lack of efficacy and/or dose-limiting adverse events. Indeed, for many of these compounds, it is likely that the maximum tolerated dose is either subtherapeutic or at the very bottom of the efficacy dose-response curve. Thus, a significant ongoing challenge that faces the pharmaceutical industry is to synthesize compounds with therapeutic ratios that are superior to roflumilast. Several strategies are being considered, but clinically effective compounds with an optimal pharmacophore have not, thus far, been reported. In this chapter, alternative means of harnessing the clinical efficacy of PDE4 inhibitors are described. These concepts are based on the assumption that additive or synergistic anti-inflammatory effects can be produced with inhibitors that target either two or more PDE families or with a PDE4 inhibitor in combination with other anti-inflammatory drugs such as a glucocorticoid.

Phosphodiesterase 4 Inhibitors Augment the Ability of Formoterol to Enhance Glucocorticoid-Dependent Gene Transcription in Human Airway Epithelial Cells: A Novel Mechanism for the Clinical Efficacy of Roflumilast in Severe Chronic Obstructive Pulmonary Disease

“…In concluding, it is appropriate to acknowledge that, although LABAs and PDE4 inhibitors alone can induce a variety of proinflammatory genes, this unwanted effect could be mitigated by an ICS and may not be overly problematic (Hertz et al, 2009;Holden et al, 2010). Thus, in severe COPD, the clinical efficacy of an ICS, a LABA, and a PDE4 inhibitor in combination may be attributable, in part, to their collective actions on gene transcription (Giembycz and Newton, 2011). Fig.…”

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

“…One candidate that could deliver therapeutic benefit is PDE3, for which inhibitors were developed for the treatment of dilated cardiomyopathy (Movsesian and Alharethi, 2002). Because PDE3 inhibitors are also bronchodilators, dual PDE3/PDE4 inhibition could produce both bronchodilator and anti-inflammatory activities (Banner and Press, 2009;Giembycz and Newton, 2011). Indeed, support for this concept was recently reported in trials using the dual PDE3/PDE4 inhibitor, RPL554, in healthy human volunteers and in patients with asthma or COPD (Franciosi et al, 2013).…”

Concurrent Agonism of Adenosine A2Band Glucocorticoid Receptors in Human Airway Epithelial Cells Cooperatively Induces Genes with Anti-Inflammatory Potential: A Novel Approach to Treat Chronic Obstructive Pulmonary Disease

“…realized with an ICS/adenosine A 2B -receptor agonist combination therapy through their individual, collective, and often cooperative actions on gene transcription (Giembycz and Newton, 2011).…”