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have all been implicated in stabilizing these dual states (Laliberte et al. 2000 ). A
consistent finding is that the high-affinity conformation is usually reduced in
truncated PDE4 enzymes, indicating that the amino terminus of PDE4 exerts
important constraints on the conformation of the catalytic domain (Conti et al.
2003 ). Whether these sites can be flexibly interconverted or are “fixed” in perpetuity
will impact considerations regarding future design of PDE inhibitors targeting these
PDEs. The dual-affinity state of PDE4s has been used in the PDE4 field as a guiding
criterion to predict therapeutic windows of PDE4 inhibitors under development with
respect to undesirable side effects of PDE4 inhibitors that have been associated with
HARBS. It seems likely that isoforms of other PDE families will also have multiple
conformations that exhibit varied affinities for particular inhibitors.
3 Design of PDE Inhibitors
3.1
Inhibitor Design
Emerging appreciation of the many factors that contribute to the physiologically
relevant action of PDEs has expanded options for development of new inhibitors.
Medicinal chemists are now setting goals for design of a spectrum of inhibitors that
selectively target either particular PDE catalytic sites, individual allosteric sites such
as the GAFs in PDEs 2, 5, 6, 10, or 11, UCRs in PDE4, a combination of the catalytic
sites and regulatory domains, or sites that provide for PDE interactions with pro-
teins/lipids to localize the PDE to particular regions of the cell (Burgin et al. 2010 ;
Keravis and Lugnier 2010 ; Verhoest et al. 2009 ). Even with the availability of
a number of clinically approved inhibitors that are selective and potent for a parti-
cular PDE family, for example, PDE5, development of a different class of inhibitors
may be needed to address specific pharmacokinetic needs in optimizing use in diverse
medical regimens, for example, compounds with improved bioavailability, slowed
clearance, improved stability, brain penetration, etc. (Owen et al. 2009 ). Moreover,
new classes of inhibitors that block only a portion of a particular PDE activity may
have merit that has not been appreciated previously (Burgin et al. 2010 ).
Traditionally, medicinal chemists have generated compounds that directly com-
pete with cN substrate for access to the catalytic sites of PDEs. This has primarily
been achieved by systematically modifying a chemical scaffold derived from
compounds known to interact with or inhibit PDE catalytic activity. The trial-
and-error approach using myriad derivatives of a lead scaffold has successfully
produced numerous potent and selective PDE inhibitors with diverse structural
characteristics; many of these compounds incorporate the purine of the cNs as the
basic scaffold with the goal of developing inhibitors that are substrate mimics but
that also include additional elements to enhance affinity and selectivity for a
particular group of PDEs (Fig. 6 ). However, selective inhibitors for most PDE
families are still not commercially available despite the great need for their use in
biochemical investigations and clinical settings.
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