Phosphodiesterase Inhibitors in the Treatment of Inflammatory Diseases - Phosphodiesterases as Drug Targets - page 394

Houslay et al. 2005 ;Wangetal. 2007 ). One possibility might be to exploit
subtle differences between the interaction of these inhibitors with the catalytic
active site. Alternatively, compounds that inhibit catalysis by targeting regions
outside the catalytic site may be possible. Compounds that selectively interact
with the N terminal regions of the respective PDE4, which contain phosphory-
lation sites and/or protein binding sequences, might indirectly interfere with PDE4
activity (Houslay et al. 2005 ). Moreover, inhibitors may act through a combined
interaction with residues in regions that fold over or near the catalytic site, e.g.,
UCR2 which provides a regulatory region unique to PDE4 enzymes as well as
some residues in the catalytic domain (Kranz et al. 2009 ;Burginetal. 2010 ).
PDE4 is expressed in a number of cell types that are considered important in
the pathogenesis of inflammatory disease (Table 1 ). It might reasonably be argued
that targeting the inhibition of PDE4 could potentially suppress the function of
numerous cell types. However, it is well known that other PDE enzymes are also
expressed in these cells and the contribution of other PDEs to cell function (e.g.,
PDE3, PDE7) in the context of regulating inflammatory cell function is also being
explored (Smith et al. 2004 ; Boswell-Smith et al. 2006a ; Banner and Press 2009 ).
Although it would seem prudent to develop subtype selective PDE4 inhibitors in
attempts to maximize therapeutic benefit at the expense of adverse effects, there is
also the possibility that nonselective PDE inhibitors might offer a better approach in
targeting multiple target cells in the disease process. Indeed, it has been suggested
that clozapine is a better antipsychotic than newer generation atypical antipsycho-
tics because this drug targets numerous receptors and as such, has been described as
a “magic shotgun” for the treatment of schizophrenia (Roth et al. 2004 ).
3 Asthma and PDE4
The underlying pathophysiological features of asthma are a consequence of the
contribution of numerous cells including the epithelium, dendritic cells, T-lympho-
cytes, eosinophils, mast cells, and airway smooth muscle. Thus, there is a complex
web of interconnecting interactions between different cell types and inflammatory
mediators. Whilst glucocorticosteroids remain the mainstay treatment of this
disease, there still remains a group of asthmatics with poor symptom control despite
treatment with these drugs (Barnes 2008 ). It is therefore of interest that many of the
cell types illustrated in Table 1 express PDE4 and inhibition of this enzyme family
can suppress the function of these cells.
A number of studies have investigated whether the pathogenesis of asthma
might be a consequence of increased PDE4 protein expression and activity.
This hypothesis had some currency in view of studies in the field of dermatology,
which purported to demonstrate the expression of a novel and distinct monocyte-
derived cAMP-PDE obtained from individuals with atopic dermatitis. Mono-
cytes from these individuals had increased functionality and this corresponded
with the presence of protein with increased PDE activity. This was thought to be