Dual PDE34 and PDE4 Inhibitors
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Basic & Clinical Pharmacology & Toxicology Doi: 10.1111/bcpt.12209 MiniReview Dual PDE3/4 and PDE4 Inhibitors: Novel Treatments For COPD and Other Inflammatory Airway Diseases Katharine H. Abbott-Banner1 and Clive P. Page2 1Verona Pharma plc, London, UK and 2Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King’s College London, London, UK (Received 2 December 2013; Accepted 30 January 2014) Abstract: Selective phosphodiesterase (PDE) 4 and dual PDE3/4 inhibitors have attracted considerable interest as potential thera- peutic agents for the treatment of respiratory diseases, largely by virtue of their anti-inflammatory (PDE4) and bifunctional bron- chodilator/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 sub- type 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. Chronic obstructive pulmonary disease (COPD) is a major health and faster disease progression, including decline in lung cause of morbidity and mortality and is increasing in preva- function and a higher risk of death [5]. There is also an lence. The WHO estimates that by 2020, COPD will be the increasing concern that the regular use of corticosteroids to third leading cause of death and the fifth leading cause of dis- treat patients with COPD makes such patients more suscepti- ability worldwide [1]. The disease is characterized by progres- ble to infections such as pneumonia [6]. sive airflow obstruction resulting from mucosal inflammation Chronic obstructive pulmonary disease is considered to be and oedema, bronchoconstriction, mucus hypersecretion and among the costliest inpatient conditions, with costs in the UK loss of elastic recoil. estimated to be £800 million, over half of which relates to Short-acting b2 agonists and muscarinic receptor antagonists hospital-based care. COPD is also estimated to be responsible are the first line of treatment, and as the disease progresses, for 24 million lost working days/year. Thus, there is a high long-acting b2 agonists (LABAs) and muscarinic antagonists unmet medical need that requires novel effective therapies [2]. (LAMAs), with the combination of a LABA and a LAMA, Inflammation is a characteristic feature of COPD that contrib- often becoming necessary as a maintenance therapy. In addi- utes to the airway obstruction and lung tissue destruction. tion, LABAs are typically used in combination with inhaled Whilst CD68+ macrophages and CD8+ T-lymphocytes are the corticosteroids (ICS) [2]. Despite the beneficial effects of these predominant cells in the bronchial mucosa of patients with therapies and their various combinations, modest beneficial COPD, the presence of other inflammatory cells such as effects on health-related quality of life and FEV1 have been B-lymphocytes, neutrophils and dendritic cells, together with observed [3], and corticosteroids are relatively ineffective at increased levels of pro-inflammatory mediators (e.g. IL-6, suppressing the airway wall thickening and luminal occlusion IL-1b, TNF-a, Gro-a, MCP-1, IL-8 and IL-32) in the lung in patients with COPD [4] and the consequent disease progres- [7–9], and increased levels of IL-1b, IL-6 and TNF-a in the sion. Indeed, most patients with COPD remain symptomatic blood, has also been observed. This inflammatory response and experience exacerbations of their disease, characterized by persists even in the absence of overt infection [10]. increased airway obstruction and worsening lung function, Exacerbations of COPD reflect a worsening of the underly- associated with enhanced airways inflammation. Patients with ing chronic inflammation in the airways and are characterized severe COPD and frequent exacerbations experience poorer by marked elevations in neutrophils and their products (e.g. neutrophil elastase) in the airways [11,12], together with Author for correspondence: Katharine Helen Abbott-Banner, Verona a Pharma plc, Suite 21, Alpha House, 100 Borough High Street, a significant increase in cytokines such as IL-8 and TNF- London, SE1 1LB, UK (e-mail [email protected]). which are known to act as chemoattractants for neutrophils © 2014 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society) 2 KATHARINE H. ABBOTT-BANNER AND CLIVE P. PAGE MiniReview [11]. Interestingly, there is a significant correlation between cells (e.g. neutrophils, eosinophils) [43–46], there is little the percentage of neutrophils in bronchoalveolar lavage (BAL) evidence for selective PDE3 inhibitors inhibiting inflammatory fluid and severity of airways obstruction assessed by FEV1/ cell function. However, there is growing evidence to suggest FVC ratio [11]. Increases in eosinophils have also been that dual inhibition of PDE3 and PDE4 can be additive or reported in patients undergoing exacerbations [13]. even synergistic at suppressing inflammatory mediator release Mucus hypersecretion and reduced mucociliary clearance from other cell types which also express PDE3 that are are also distinctive features of COPD that are thought to con- thought to play a role in COPD (e.g. macrophages, dendritic tribute to airway obstruction and the progressive decline in cells, epithelial cells, lymphocytes, airway smooth muscle cells FEV1. Very importantly, ICS do not appear to have any effect and endothelial cells) [27,39,47–50]. on the accelerated decline in FEV1 [14], suggesting the need PDE3 inhibitors cause bronchodilation in man [51], and there for novel classes of anti-inflammatory drugs to reduce the pro- is evidence from pre-clinical studies to suggest that combined gression of this debilitating disease. It is interesting to note inhibition of PDE3 and PDE4 suppresses spasmogen-induced that cystic fibrosis transmembrane conductance regulator contraction of human and bovine airway smooth muscle, in a (CFTR), a chloride ion channel which plays an integral role in synergistic fashion [52,53]. PDE3 and PDE4 inhibitors have controlling the electrolyte/fluid balance and regulating muco- also been shown to activate CFTR-mediated ClÀ secretion, sug- ciliary clearance [15], is reduced in COPD patients, with gesting they may be able to stimulate mucociliary clearance expression inversely correlating with disease severity [16]. [15]. This diverse spectrum of biological effects has thus impli- Cyclic adenosine monophosphate (cAMP) and cyclic guano- cated PDE4 and PDE3/4 inhibitors as potential therapeutic sine monophosphate (cGMP) regulate a variety of cellular pro- agents for a range of disease indications involving inflamma- cesses including airway smooth muscle relaxation and tion and altered mucus production such as COPD, asthma and inflammatory mediator release [17]. The phosphodiesterase cystic fibrosis. Indeed, both the FDA and EMEA approved (PDE) enzyme family hydrolyses, cAMP and cGMP, to inac- roflumilast-n-oxide, an orally administered selective PDE4 tive 50AMP and 50GMP, respectively, and thus, inhibition of inhibitor in 2010 for the maintenance treatment of severe PDEs represents a potential mechanism by which cell func- COPD associated with bronchitis and a history of frequent tions such as airway smooth muscle relaxation and inflamma- exacerbations, as an add-on to standard treatment. Orally tory mediator release can be modulated [18]. 11 PDE gene administered PDE4 inhibitors, do, however, have a low thera- families have been identified, denoted PDE1-11, which differ peutic ratio, with particular concerns for the gastrointestinal in primary structures, affinities for cAMP and cGMP, side effects which to date have stopped their development or responses to specific effectors, sensitivities to specific inhibi- limited their wider use. It is conceivable therefore that adminis- tors and mechanisms of regulation [19]. Each family contains tration of PDE inhibitors, particularly a dual PDE3/4 inhibitor at least one member, and in some cases, the members are by the inhaled route, may offer increased efficacy with a products of more than one gene. reduced side effect potential versus an orally administered PDE4 is a low km (~1–10 lM) cAMP-specific PDE that PDE4 inhibitor. only has a weak affinity for cGMP (km > 50 lM). The PDE4 family is comprised of four genes (PDE4A, B, C, D), with Pre-clinical Data with PDE3 and PDE4 Inhibitors each gene having multiple splice variants. PDE4 gene prod- ucts have a broad tissue distribution; including the brain, gas- Bronchodilation. trointestinal tract, spleen, lung, heart, testis and