Abstract
PDE4 inhibitors can suppress a variety of inflammatory cell functions that contribute to their anti-inflammatory actions in respiratory diseases like chronic obstructive pulmonary disease (COPD) and asthma. The systemically delivered PDE4 inhibitor roflumilast has been approved for use in a subset of patients with severe COPD with chronic bronchitis and a history of exacerbations. Use of systemically delivered PDE4 inhibitors has been limited by systemic side effects. Inhaled PDE4 inhibitors have been considered as a viable alternative to increase tolerability and determine the maximum therapeutic potential of PDE4 inhibition in respiratory diseases.
Highlights
Phosphodiesterase (PDE) enzymes metabolize the intracellular second messengers cyclic adenosine monophosphate and cyclic guanosine monophosphate
Therefor Phosphodiesterase 4 (PDE4) inhibitors are an effective therapeutic strategy for inflammatory respiratory diseases as they inhibit the hydrolysis of cyclic adenosine monophosphate (cAMP) (Rall and Sutherland, 1958), effectively increasing levels of cAMP, and activating downstream phosphorylation cascades (Li et al, 2018) which relax airway smooth muscle and inhibit inflammation (Houslay et al, 2005; Mulhall et al, 2015)
PDE4 inhibitors block the breakdown of cAMP and decrease airway inflammation
Summary
Phosphodiesterase (PDE) enzymes metabolize the intracellular second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). AWD-12-281 was the first moderately potent PDE4 inhibitor (IC50 = 9.7 nM) designed for inhaled delivery (Draheim et al, 2004; Gutke et al, 2005) and showed preclinical efficacy in a variety of species (Kuss et al, 2003) It was in clinical development for asthma and COPD results are unavailable in the public domain. 12b has preclinical anti-inflammatory activity in the lung with high plasma protein binding and low bioavailability to reduce systemic side effects (De Savi et al, 2014) It is unclear if this compound is progressing into clinical trials as AstraZeneca currently has no PDE4 inhibitors in their pipeline. The results of the phase III clinical trials are eagerly awaited
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