Phosphodiesterase Inhibitors: Factors That Influence Potency, Selectivity, and Action - Phosphodiesterases as Drug Targets - page 56

splice variants of PDE1C differs by threefold: PDE1C1 (IC 50 ¼ 101 nM) versus

PDE1C4/5 (IC 50 ¼ 36 nM) (Yan et al. 1996 ).

PDE4 inhibitors can also exhibit quite different potencies for the various mem-
bers of this family. Cilomilast, a highly selective inhibitor of the PDE4 family,
exhibits significantly higher potency (7- to 27-fold) toward PDE4D (IC 50 ~ 12 nM)
compared to that for PDE4A (IC 50 ~ 115 nM), PDE4B (IC 50 ~ 86 nM), or PDE4C
(IC 50 ~ 308 nM) (Torphy 1998 ). Inhibitors that show good selectivity for PDE4D
over PDE4B have also been identified: NVP-ABE171 is 20-fold selective for
PDE4D over PDE4B (Trifilieff et al. 2002 ) and CP-671305 is 95-fold selective
for PDE4D over PDE4B (Kalgutkar et al. 2004 ; Zhang 2006 ). Moreover, D159687,
a compound recently reported by investigators at deCode Genetics, is highly
selective for PDE4D7 versus PDE4A1, PDE4B1, and PDE4C1 (93-, 54-, and
250-fold difference in potency, respectively) (Burgin et al. 2010 ). The structural
subtleties that provide for these differences in such closely related enzymes are
typically not fully understood; they could relate to differences in the catalytic
site pocket or reflect the influence of interactions of the inhibitors with regions
outside the catalytic pocket as occurs for the D159687 compound or interaction
with protein binding partners and posttranslational modification (Burgin et al.
2010 ; Houslay 2001 ; Houslay and Adams 2003 ; Houslay et al. 2005 , 2007 ).
Exploiting these differences may open novel opportunities for the development
of more selective inhibitors. However, each modest advance in devising a com-
pound that shows selectivity among PDEs is just the beginning in the efforts to
develop a compound with pharmacokinetic and biochemical features suitable for
clinical use.

2 Factors That Impact Catalytic Site Function and Potency
of Inhibitor Action

PDE catalytic site functions can be modified by many processes, including post-
translational modifications, change in the cellular milieu (pH or redox conditions),
interaction with activators (e.g., calcium/calmodulin, cGMP, or phosphatidic acid),
binding to other proteins, and exposure to drugs (Burgin et al. 2010 ; Houslay 2001 ;
Houslay and Adams 2003 , 2010 ; Houslay et al. 2005 , 2007 ). The influence of these
factors on the potencies of inhibitors for any PDE is not fully understood and effects
identified for a particular inhibitor frequently do not apply to other inhibitors of that
PDE family. Consequently, environmental or posttranslational effects on each
inhibitor must be assessed independently. The state of oligomerization of a PDE
may also be a determinant of the pharmacological properties of an inhibitor (Burgin
et al. 2010 ; Richter and Conti 2004 ; Rybalkina et al. 2010 ). Moreover, it is clear that
insights derived from structural studies of isolated catalytic domains of PDEs do not
always reveal all of the important contact points that could be exploited in the
design of new inhibitors (Blount et al. 2006 ; Burgin et al. 2010 ).