Biology Reference
In-Depth Information
2.5 Nonselective PDE Inhibition
A logical extension to the aforementioned discussion on dual-selective inhibitors is
to consider whether nonselective compounds would have even greater efficacy in
combating chronic airway inflammation. It is well reported that theophylline may
exert anti-inflammatory activity in human subjects with asthma when given at sub-
bronchodilator doses where the plasma concentration is between 5 and 10
m
g/ml.
Although this beneficial effect is often attributed to mechanisms unrelated to PDE
inhibition, this interpretation is unnecessary. Indeed, theophylline even at a concen-
tration of 5
m
g/ml (27
m
M), and taking into account plasma protein binding, will
inhibit, albeit modestly, PDEs 1-5 by up to ~20% depending on the isoenzyme. Thus,
in addition to any beneficial effects produced by the inhibition of each PDE in
isolation (see Sects.
2.1
-
2.4
), the probability for functional additivity and, indeed,
synergy when multiple PDEs are inhibited concurrently in the same cell types cannot
be overstated (Fig.
2
) (Giembycz
2005b
). Accordingly, it is not unreasonable to
believe that second-generation, nonselective PDE inhibitors could exhibit superior
clinical efficacy over theophylline or compounds that selectively target PDE4.
Indeed, simultaneous inhibition of multiple PDEs should exert clinically relevant
effects on multiple proinflammatory processes including airway remodeling (PDE1-
regulated), endothelial cell permeability (PDE2-regulated), mast cell stabilization
(PDE3-mediated), and remodeling of the pulmonary vasculature (PDE5-regulated).
Anti-proliferative ?
Pulmonary Vasodilator ?
Anti-inflammatory?
PDE1
PDE2
Bronchodilator
Anti-thrombotic
Pulmonary Vasodilator ?
Anti-inflammatory ?
PDE7
PDE3
PDE5
PDE4
Pulmonary Vasodilator
Anti-thrombotic
Anti-inflammatory
Pulmonary Vasodilator?
Fig. 2 Functional consequences of selective phosphodiesterase (PDE) inhibition in relation to the
treatment of COPD. The cartoon shows clinically beneficial effects that may be produced
following the selective inhibition of PDEs 1, 2, 3, 4, 5, and 7. Additive and/or synergistic effects
may be produced if two or more PDEs are inhibited concurrently (
reversible arrows
). For example,
it is well established that a PDE3 inhibitor and a PDE7 inhibitor will potentiate the effect of a
PDE4 inhibitor. Similar interactions have been reported for other PDEs. Accordingly, a nonselec-
tive PDE inhibitor is predicted to have a beneficial clinical impact on multiple facets of the disease
process and may be a far superior drug that inhibits PDE4 selectively
