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lung macrophages together with several cell lines including HUT-78 (T-cell) and
BEAS-2B (epithelial) are also PDE7A
+
(Secchiero et al.
2000
; Smith et al.
2003
).
In contrast, PDE7A expression is seemingly much lower in human neutrophils
since it was not identified by western blotting, although the protein was clearly
labeled using immunoconfocal laser microscopy (Smith et al.
2003
). This more
sensitive technique has also been employed to determine the expression profile of
PDE7A in cells present in sputum and bronchoalveolar lavage fluid in which
neutrophils from both normal subjects and individuals with asthma and COPD
were clearly labeled (Smith et al.
2003
).
The coincident expression of PDE7 and PDE4 in many cells relevant to the
pathogenesis of chronic airway inflammation nourished the idea that selective
PDE7A inhibitors could be anti-inflammatory with an improved adverse-effect
profile of PDE4 inhibitors (Giembycz and Smith
2006a
,
b
). However, despite the
discovery of PDE7 in the early 1990s (Michaeli et al.
1993
), there were until 2001
surprisingly few reports of selective inhibitors. However, many examples of com-
pounds with PDE7 inhibitory activity have now been described (reviewed in
Giembycz and Smith
2006a
,
b
; Gil et al.
2008
; Vergne et al.
2005
) and some of
these have been evaluated in preclinical models of inflammation including BRL
50481 (Smith et al.
2004
), PF 0332040 (Jones et al.
2006
), ABS16165 (Goto et al.
2009
; Kadoshima-Yamaoka et al.
2009a
,
b
,
c
), T-2585 (Nakata et al.
2002
), and
BMS 586353 (Yang et al.
2003
). What has emerged thus far from these investiga-
tions is controversy. Thus, PDE7 inhibitors have been reported to be active and
inactive in suppressing indices of inflammation in vitro and in vivo. Nevertheless,
of potential interest is that although the PDE7A inhibitor, BRL 50481, did not
attenuate the proliferation of human T-cells per se, it significantly augmented
the antimitogenic and cAMP-elevating activity of the PDE4 inhibitor, rolipram
(Smith et al.
2004
). Similarly, the suppression by PDE4 inhibitors of tumor necrosis
factor-
a
(TNF-
a
) release from LPS-stimulated human monocytes and lung macro-
phages was significantly enhanced by BRL 50481 (Smith et al.
2004
). Collectively,
these data are reminiscent of the behavior of PDE3 inhibitors in human T-cells (see
Sect.
2.2
) and tempt speculation that additive or even synergistic anti-inflammatory
effects could be realized with a dual PDE4/PDE7 inhibitor over a PDE4 inhibitor
alone (Giembycz
2005a
; Vijayakrishnan et al.
2007
). Moreover, it is also possible
that this dual PDE inhibition approach would increase tolerability and avoid the
potential cardiovascular complications that are of concern with dual PDE3/PDE4
inhibitors (described in Sect.
2.2
).
Despite the potential therapeutic utility of PDE4/PDE7 inhibitors, very few
studies have investigated the biology of these compounds and whether they are,
in fact, superior to selective PDE4 inhibitors in suppressing indices of inflamma-
tion. Only compound 6 (YM-393059; Fig.
1
), which inhibits PDE4 and PDE7
with IC
50
values of 630 and 14 nM, respectively (Yamamoto et al.
2006b
), has
demonstrated efficacy in preclinical models of inflammation with a reduced
emetic liability (Yamamoto et al.
2006a
,
b
; Yamamoto et al.
2007a
). However, it
is difficult to determine the extent to which inhibition of PDE7 contributed to these
desirable outcomes.
