Open AccessJournal Article
Anti-Inflammatory and Immunomodulatory Potential of the Novel PDE4 Inhibitor Roflumilast in Vitro
TLDR
Compared with neutrophils and eosinophils, representing the terminal inflammatory effector cells, the relative potency of roflumilast and its N-oxide for monocytes, CD4+ T cells, and dendritic cells is substantially higher compared with cilomilasts and rolipram, probably reflecting an improved immunomodulatory potential.Abstract:
From a series of benzamide derivatives, roflumilast (3-cyclo-propylmethoxy-4-difluoromethoxy-N-[3,5-di-chloropyrid-4-yl]-benzamide) was identified as a potent and selective PDE4 inhibitor. It inhibits PDE4 activity from human neutrophils with an IC(50) of 0.8 nM without affecting PDE1 (bovine brain), PDE2 (rat heart), and PDE3 and PDE5 (human platelets) even at 10,000-fold higher concentrations. Roflumilast is almost equipotent to its major metabolite formed in vivo (roflumilast N-oxide) and piclamilast (RP 73401), however, more than 100-fold more potent than rolipram and Ariflo (cilomilast; SB 207499). The anti-inflammatory and immunomodulatory potential of roflumilast and the reference compounds was investigated in various human leukocytes using cell-specific responses: neutrophils [N-formyl-methyl-leucyl-phenylalanine (fMLP)-induced formation of LTB(4) and reactive oxygen species (ROS)], eosinophils (fMLP- and C5a-induced ROS formation), monocytes, monocyte-derived macrophages, and dendritic cells (lipopolysaccharide-induced tumor necrosis factor-alpha synthesis), and CD4+ T cells (anti-CD3/anti-CD28 monoclonal antibody-stimulated proliferation, IL-2, IL-4, IL-5, and interferon-gamma release). Independent of the cell type and the response investigated, the corresponding IC values (for half-maximum inhibition) of roflumilast were within a narrow range (2-21 nM), very similar to roflumilast N-oxide (3-40 nM) and piclamilast (2-13 nM). In contrast, cilomilast (40-3000 nM) and rolipram (10-600 nM) showed greater differences with the highest potency for neutrophils. Compared with neutrophils and eosinophils, representing the terminal inflammatory effector cells, the relative potency of roflumilast and its N-oxide for monocytes, CD4+ T cells, and dendritic cells is substantially higher compared with cilomilast and rolipram, probably reflecting an improved immunomodulatory potential. The efficacy of roflumilast in vitro and in vivo (see accompanying article in this issue) suggests that roflumilast will be useful in the treatment of chronic inflammatory disorders such as asthma and chronic obstructive pulmonary disease.read more
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Journal ArticleDOI
Cyclic Nucleotide Phosphodiesterases: Molecular Regulation to Clinical Use
Andrew T. Bender,Joseph A. Beavo +1 more
TL;DR: Basic biochemical properties, cellular regulation, expression patterns, and physiological functions of the different PDE isoforms will be discussed and how these properties relate to the current and future development of PDE inhibitors as pharmacological agents is especially considered.
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Cyclic nucleotide phosphodiesterase (PDE) superfamily: a new target for the development of specific therapeutic agents.
TL;DR: By inhibiting specifically the up-regulated PDE isozyme(s) with newly synthesized potent and isozyme-selective PDE inhibitors, it may be potentially possible to restore normal intracellular signaling selectively, providing therapy with reduced adverse effects.
Journal ArticleDOI
Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials
Peter M.A. Calverley,Klaus F. Rabe,Udo-Michael Goehring,Søren Kristiansen,Leonardo M. Fabbri,Fernando J. Martinez +5 more
TL;DR: This investigation investigated whether roflumilast would reduce the frequency of exacerbations requiring corticosteroids in patients with COPD and found that targeted specific therapies could improve disease management.
Journal ArticleDOI
Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials
Leonardo M. Fabbri,Peter M.A. Calverley,José Luis Izquierdo-Alonso,Daniela S. Bundschuh,Manja Brose,Fernando J. Martinez,Klaus F. Rabe +6 more
TL;DR: Roflumilast improves lung function in patients with COPD treated with salmeterol or tiotropium, and could become an important treatment for these patients.
Journal ArticleDOI
Cyclic nucleotide phosphodiesterases.
TL;DR: The available in vitro, preclinical, and clinical data supporting the potential for selective PDE inhibitors as immunomodulatory agents are reviewed.
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