Editorial: Phosphodiesterases as Drug Targets in Airway and Inflammatory Diseases

Phosphodiesterases as Drug Targets in Airway and Inflammatory DiseasesRecently, several new drugs have been introduced to treat obstructive lung diseases associated with inflammation (e.g., bronchial asthma, chronic obstructive pulmonary disease [COPD]), including long-acting bronchodilators, corticosteroids and monoclonal antibodies.Despite these new medicines, there are still patients who might benefit from a more selective approach to treatment given that this may be accompanied by fewer adverse effects, especially when a combination of drugs is required to manage severe disease.The possibility that inhibiting certain phosphodiesterase (PDE) isoenzymes (in particular PDE3 and PDE4) and, thereby, increasing the concentration of cyclic adenosine monophosphate (cAMP) in specific tissues and organs, may have therapeutic benefit has gained general acceptance over the last 30 years.Indeed, PDEs have become attractive drug targets because an increase in cAMP can relax smooth muscle and suppress inflammation.The articles in this series of mini-reviews focus on the involvement of various PDE isoforms in the mechanisms underlying inflammatory and other airway diseases.As described by Beute et al., PDE3 plays a critical role in basophil and mast cell degranulation and, therefore, its inhibition by a small molecule inhibitors such as enoximone may be a viable treatment option in allergic airway inflammation.Similarly, another selective PDE3 inhibitor RPL554 (ensifentrine) has been intensively tested during last years and exhibits both bronchodilator and anti-inflammatory activity in vitro and in vivo assays.The benefits of inhaled ensifentrine in clinical studies with asthma and COPD patients is reviewed by Phillips and showed predominantly bronchodilator effects without reliable evidence for anti-inflammatory activity usually associated with PDE4 inhibition (Cazzola et al., 2019).This can be explained by moderately potent PDE3 inhibition but only weakly potent PDE4 inhibition of this agent, as described by Boswell-Smith et al. (2006).Currently, roflumilast is the only selective PDE4 inhibitor that has been approved for the treatment of a particular subset of patients with COPD.Disease guidelines recommend that roflumilast be used as an add-on therapy in people categorized as high risk, having severe, symptomatic COPD in whom exacerbations occur despite regular treatment with a combination of a long-acting β 2 -adrenoceptor agonist (LABA), a long-acting muscarinic receptor antagonist and an inhaled corticosteroid.However, roflumilast has a low therapeutic ratio and ways to improve effectiveness and tolerability are needed.Possibilities include the development of dual-or multispecificity agents.Another potential approach to improve the tolerability and therapeutic index is to develop PDE4 inhibitors for inhaled administration.Several examples exist and some have advanced to clinical trials for the treatment of asthma and COPD.Phillips, in his brief update,

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