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lead to a reduction in pulmonary vascular resistance (see Sect. 2.2 ). In this respect,
it is significant that PDE1A and PDE1C are upregulated in “remodeled” pulmo-
nary artery vessels harvested from patients with idiopathic pulmonary hyperten-
sion (PH) (Schermuly et al. 2007 ).
2.2
Inhibition of PDE3 and PDE4
Interest in PDE3 as a target for the treatment of asthma and COPD originated from
the finding that selective PDE3 inhibitors promote bronchodilation in humans
(Bardin et al. 1998 ; Fujimura et al. 1995 ; Leeman et al. 1987 ; Myou et al. 1999 ).
Thus, mechanistically, inhibitors that block both PDE3 and PDE4 should improve
lung function, by promoting airway smooth muscle relaxation, and suppress inflam-
mation, respectively. Accordingly, such drugs are predicted to have superior clinical
efficacy over compounds that selectively block PDE4. Furthermore, a potentially
more significant effect is that PDE3 may also have clinically relevant actions on
certain proinflammatory and immune cells especially during concurrent PDE4
inhibition. For example, T-lymphocytes, macrophages, monocytes, epithelial and
endothelial cells, dendritic cells, and airway myocytes coexpress PDE3 and PDE4
(Banner and Press 2009 ; Torphy 1998 ). In vitro studies have shown that while
PDE3 inhibitors generally have little or no effect on T-cell proliferation or on IL-2
generation, they significantly enhance the repressive effect of a PDE4 inhibitor
(Giembycz et al. 1996 ; Robicsek et al. 1991 ). Similar data have been reported for
the inhibition of proinflammatory responses in human alveolar macrophages
(Schudt et al. 1995 ), monocyte-derived dendritic cells (Gantner et al. 1999 ), airway
epithelial cells (Wright et al. 1998 ), human lung fibroblasts (Selige et al. 2010 ), and
human lung microvascular endothelial cells (Blease et al. 1998 ).
Several dual-selective inhibitors of PDE3 and PDE4 have been developed and
evaluated in humans including zardaverine, ben(z)afentrine, tolafentrine, and
pumafentrine (see Chap. 6.2 and Banner and Press 2009 ). Since the early 2000s,
there has been a dearth of peer-reviewed data from which to gauge the clinical
progress of these molecules and one must assume that the development of many of
those originally described compounds has been discontinued. However, the devel-
opment of new PDE3/PDE4 candidates continues, suggesting that early testing in
humans has begun or will likely follow in the short term. For example, the
pharmacology of two long-acting pyrimido[6,1- a ]isoquinolin-4-ones, which are
derivatives of trequensin and are protected by a patent from Verona Pharma
(Oxford and Jack 2000 ), have been described (Boswell-Smith et al. 2006 ). Com-
pound 2 (RPL 554; Fig. 1 ) is a very potent PDE3 inhibitor (IC 50 ¼
400 pM) with an
IC 50 (1.5 m M) that is
1.5 m M).
Currently, this compound is in Phase I/IIa studies for allergic rhinitis and asthma
(Pages et al. 2009 ). Given the isoenzyme selectively of this compound, it seems
likely that the dominant activity of 2 will be PDE3 inhibition, which might limit
3,000-fold lower for inhibition of PDE4 (IC 50 ¼
>
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