Biology Reference
In-Depth Information
development of more selective inhibitors, for example, development of inhibitors
that selectively target the catalytic sites of the respective PDE4 isoforms, which
have clear clinical implications. Although this approach has been slow to produce
better inhibitors, some progress is being made as evidenced by the recent emergence
of a specific, a potent PDE10 inhibitor (Verhoest et al.
2009
), an improved PDE5
inhibitor (Owen et al.
2009
), and new PDE4 inhibitors (Burgin et al.
2010
).
3.2
Inhibitor Selectivity and Potency
The goals involved in generating desirable PDE inhibitors include selectivity and
potency. Selectivity is a key feature in most instances; typically, a compound that
exhibits potency for one PDE that is 50- to 100-fold greater than potency of
inhibition for other PDEs is deemed to be a “specific” inhibitor. However, this
measure is not always rigorously applied in the literature. Although sildenafil and
vardenafil are commonly referred to as PDE5-selective or PDE5-specific, they also
potently inhibit PDE6 (Zhang et al.
2005
). This close overlap in function confounds
use of these compounds in studies involving visual transduction or pineal functions.
The restriction of PDE6 expression to photoreceptor cells and the pineal gland
minimizes the issue surrounding this lack of selectivity between these two families,
but it should be kept in mind for studies involving neuronal tissues or other tissues,
where PDE6 might be expressed (Bazhin et al.
2010
). Likewise, even when an
inhibitor meets the criteria of being defined as “specific” for one PDE versus
another, partial inhibition of the other PDE may come into play in the physiological
setting (Lukowski et al.
2010
).
Potency, while generally desirable, may have reasonable limitations. A potent
inhibitor is likely to require lower doses to achieve the desired effect thus translat-
ing into lower drug exposure for the patient and lesser chance for unanticipated
reactions. However, to inhibit a meaningful portion of the activity of a PDE in a
tissue, there will have to be sufficient circulating inhibitor to block a significant
portion of that activity. It has been conjectured that high-affinity interaction
between an inhibitor and a PDE could foster increased concentration of the inhibitor
in the cell until the PDE is saturated, that is, the PDE would simply soak up the
inhibitor as long as high-affinity sites are available (Francis et al.
2008
). In these
cases, the absolute concentration of the PDE in a particular cell would determine
the amount of the high-affinity inhibitor localized to the cellular milieu.
4
Interactions of PDE Inhibitors with Multiple PDEs
or Non-PDE Proteins
New drugs are typically designed to selectively interact with one targeted protein,
and PDE inhibitors are no exception. However, the molecular scaffold of many
PDE inhibitors mimics the purine in cAMP and cGMP. Given the number of
