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Vol. 297, Issue 1, 267-279, April 2001
Byk Gulden, Department of Biochemistry, Konstanz, Germany
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 IC50 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 LTB4 and reactive oxygen species (ROS)],
eosinophils (fMLP- and C5a-induced ROS formation), monocytes,
monocyte-derived macrophages, and dendritic cells
(lipopolysaccharide-induced tumor necrosis factor-
synthesis), and CD4+ T cells (anti-CD3/anti-CD28 monoclonal antibody-stimulated proliferation, IL-2, IL-4, IL-5, and interferon-
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.
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