Phosphodiesterase Inhibitors for the Treatment of Asthma and Chronic Obstructive Pulmonary Disease

Abstract

Xanthines like theophylline have long been recognised as being effective drugs for the treatment of asthma and chronic obstructive pulmonary disease (COPD). They are of interest as they possess both anti-inflammatory and bronchodilator activity in the same molecule. Since the discovery of phosphodiesterases (PDEs) in the late 1950s, it has been suggested that xanthines work, in part, by acting as non-selective PDE inhibitors. However, it has also been suggested that the ability of xanthines to non-selectively inhibit PDEs contributes to their many unwanted side effects, thus limiting their use since the arrival of inhaled drugs with more favourable safety profiles. As our understanding of PDEs has improved over the last 30 years, and with the recognition that the distribution of different PDEs varies across different cell types, this family of enzymes has been widely investigated as targets for novel drugs. In particular, PDE3 in airway smooth muscle and PDE4 and PDE7 in inflammatory cells have been targeted to provide new bronchodilators and anti-inflammatory agents, respectively. This review discusses the progress made in this field over the last decade in the development of selective PDE inhibitors to treat COPD and asthma.

Targeting Neutrophils in Severe Asthma via Siglec-9

“…However, treatment with the macrolide clarithromycin does not consistently improve the condition of patients with predominantly neutrophilic severe asthma, although there is a positive effect on airway hyperresponsiveness [27]. In addition, a variety of broad-spectrum anti-inflammatory inhibitors (e.g., kinase inhibitors [28], PDE4 inhibitors [29], CXCR2 antagonists [30]) have been developed in the treatment of severe asthmatic patients. However, most of them are usually with unsatisfactory responses or appear to cause mechanism-related side-effects, which limit their clinical application [31].…”

Cigarette smoke up‐regulates PDE3 and PDE4 to decrease cAMP in airway cells

“…In animal studies, CS exposure leads to a reduced lung function, emphysema, mucus hypersecretion and induction of proinflammatory processes (Rangasamy et al ., 2009; Rinaldi et al ., 2012; Oldenburger et al ., 2014; Page, 2014; Heulens et al ., 2015). PDE4 inhibitors are currently used for the treatment of COPD, and additional compounds are under development (Page, 2014).…”

“…In animal studies, CS exposure leads to a reduced lung function, emphysema, mucus hypersecretion and induction of proinflammatory processes (Rangasamy et al ., 2009; Rinaldi et al ., 2012; Oldenburger et al ., 2014; Page, 2014; Heulens et al ., 2015). PDE4 inhibitors are currently used for the treatment of COPD, and additional compounds are under development (Page, 2014). The PDE4 inhibitor roflumilast N‐oxide partly reverses CS‐induced epithelial dysfunction (Milara et al ., 2014, 2012; Schmid et al ., 2015; Tyrrell et al ., 2015), and the PDE4 inhibitors, GPD‐1116 and piclamilast can prevent the development of CS‐induced emphysema and pulmonary hypertension in mice (Mori et al ., 2008; Seimetz et al ., 2015, p. 4).…”

New and developing non-adrenoreceptor small molecule drugs for the treatment of asthma

“…Phosphodiesterase (PDE)4 inhibitors have anti-inflammatory effects on effector cells potentially relevant to the treatment of asthma [43][44][45] . In a Phase II allergen challenge study, the oral PDE4…”