After more than two decades of research into
phosphodiesterase 4 (
PDE4) inhibitors,
roflumilast (3-cyclopropylmethoxy-4-difluoromethoxy-N-[3,5-di-chloropyrid-4-yl]-
benzamide) may become the first agent in this class to be approved for patient treatment worldwide. Within the PDE family of 11 known
isoenzymes,
roflumilast is selective for PDE4, showing balanced selectivity for subtypes A-D, and is of high subnanomolar potency. The active principle of
roflumilast in man is its dichloropyridyl N-
oxide metabolite, which has similar potency as a
PDE4 inhibitor as the parent compound. The long half-life and high potency of this metabolite allows for once-daily,
oral administration of a single, 500-microg
tablet of
roflumilast. The molecular mode of action of roflumilast--PDE4 inhibition and subsequent enhancement of cAMP levels--is well established. To further understand its functional mode of action in
chronic obstructive pulmonary disease (
COPD), for which
roflumilast is being developed, a series of in vitro and in vivo preclinical studies has been performed.
COPD is a progressive, devastating condition of the lung associated with an abnormal inflammatory response to noxious particles and
gases, particularly tobacco
smoke. In addition, according to the Global Initiative for
Chronic Obstructive Lung Disease (
GOLD), significant extrapulmonary effects, including comorbidities, may add to the severity of the disease in individual patients, and which may be addressed preferentially by orally administered remedies.
COPD shows an increasing prevalence and mortality, and its treatment remains a high, unmet medical need. In vivo,
roflumilast mitigates key
COPD-related disease mechanisms such as tobacco
smoke-induced
lung inflammation, mucociliary malfunction, lung fibrotic and emphysematous remodelling, oxidative stress, pulmonary vascular remodelling and
pulmonary hypertension. In vitro,
roflumilast N-oxide has been demonstrated to affect the functions of many cell types, including neutrophils, monocytes/macrophages, CD4+ and CD8+ T-cells, endothelial cells, epithelial cells, smooth muscle cells and fibroblasts. These cellular effects are thought to be responsible for the beneficial effects of
roflumilast on the disease mechanisms of
COPD, which translate into reduced exacerbations and improved lung function. As a multicomponent disease,
COPD requires a broad therapeutic approach that might be achieved by PDE4 inhibition. However, as a
PDE4 inhibitor,
roflumilast is not a direct
bronchodilator. In summary,
roflumilast may be the first-in-class
PDE4 inhibitor for
COPD therapy. In addition to being a non-
steroid, anti-inflammatory drug designed to target
pulmonary inflammation, the preclinical pharmacology described in this review points to a broad functional mode of action of
roflumilast that putatively addresses additional
COPD mechanisms. This enables
roflumilast to offer effective, oral maintenance treatment for
COPD, with an acceptable tolerability profile and the potential to favourably affect the extrapulmonary effects of the disease.