Biology Reference
In-Depth Information
PR Progesterone receptor
PVR Pulmonary vascular resistance
RAR/RXR Retinoic acid receptors
SABA
Short-acting b 2 -adrenoceptor agonist
1
Introduction
Since the early 1990s, there has been considerable interest in phosphodiesterase
(PDE) 4 as an intracellular target that could be exploited to therapeutic advantage
for a multitude of chronic inflammatory diseases, with asthma and chronic obstruc-
tive pulmonary disease (COPD) being primary indications (Burnouf and Pruniaux
2002 ; Doherty 1999 ; Dyke and Montana 2002 ; Giembycz 2001 ; Houslay et al.
2005 ; Huang et al. 2001 ; Souness et al. 2000 ; Torphy 1998 ). Although targeting
PDE4 with small molecule inhibitors is based on a conceptually robust hypothesis
(see references in Giembycz 2000 ), dose-limiting adverse events that include
nausea and vomiting have impeded their clinical development (Burnouf et al.
1998 ; Giembycz 2006 ). These undesirable effects are due to the inhibition of
PDE4 in nontarget tissues (Duplantier et al. 1996 ), and a fundamental challenge
that is still to be adequately met by the pharmaceutical industry is to synthesize
compounds with improved therapeutic ratios. Several strategies (not discussed
here) are being considered to dissociate the beneficial from the detrimental effects
of PDE4 inhibitors. These include restricting penetration of the inhibitor into the
central nervous system (CNS) (Aoki et al. 2001 ; Bureau et al. 2006 ), selectively
targeting among the four PDE4 isoenzyme families (Giembycz 2008 ; Srivani et al.
2008 ), the generation of “soft” inhibitors (Zhang et al. 2010 ) as originally defined
by Bodor ( 1984 ), and, more recently, the development of allosteric inhibitors,
which are predicted to have a lower emetic liability (Burgin et al. 2010 ). In an
attempt to identify the molecular targets that are responsible for adverse effects,
Merck Frosst synthesized highly emetic, quinoline-based PDE4 inhibitors that
covalently label their molecular targets following photoactivation (MacDonald
et al. 2000 ). However, even with this elegant approach, compounds with an ideal
pharmacophore have not, thus far, been reported. In this chapter, alternative means
of harnessing the clinical efficacy of PDE4 inhibitors for inflammatory lung dis-
eases are described. These concepts are based on the assumption that additive or,
ideally, synergistic anti-inflammatory effects can be realized with inhibitors of two
or more PDE families or with a PDE4 inhibitor in combination with another anti-
inflammatory drug. The overriding premise of this approach is that the therapeutic
effects of a PDE4 inhibitor could be realized at a dose lower than would normally
be required if it is used as a monotherapy. A corollary to this hypothesis is that the
PDE4 inhibitor should also have a much-improved adverse-effect profile.
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