Phosphodiesterase Inhibitors in the Treatment of Inflammatory Diseases - Phosphodiesterases as Drug Targets - page 393

(Barnes 2008 ), allergic skin diseases and psoriasis (Baumer et al. 2007 ), and
inflammatory bowel disease (Keshavarzian et al. 2007 ).
It is therefore of interest that plasma levels achieved with a dose of theophylline
that demonstrated significant anti-inflammatory activity (Sullivan et al. 1994 ) are
well below the K i for PDE inhibition and suggested that PDE4 inhibition alone does
not completely explain the clinical effectiveness of this drug (Barnes et al. 2005 ).
Nevertheless, highly potent and selective PDE4 inhibitors have been developed
to target a range of inflammatory diseases. However, targeting PDE enzymes is not
unique to inflammatory diseases as exemplified with the development and clinical
success of a number of PDE5 inhibitors for the treatment of erectile dysfunction as
exemplified by sildenafil (Boolell et al. 1996 ).
2 Phosphodiesterase 4
PDE4 is highly selective for catalyzing the hydrolysis of cAMP, which terminates
the downstream signalling of this second messenger (Houslay et al. 2007 ; Houslay
2010 ). There are 4 gene families (A, B, C, and D), where alternative mRNA
splicing and the use of distinct promoters generates more than 20 splice variants
(Houslay et al. 2007 ). While hydrolysis of cAMP is a common feature of this
family, it is clear that these isoforms can be targeted to different domains and
signalling complexes within the intracellular compartment, where they play a pivotal
role in underpinning compartmentalized cAMP signaling (Houslay 2010 ). Further-
more, their activities can be differentially regulated by phosphorylation by various
protein kinases, suggesting that these isoforms have specific functions in the control
of cellular activity (McCahill et al. 2008 ).
X-ray crystallography has resolved the catalytic domain of these enzymes,
which comprise three important domains: a bivalent metal binding pocket (Zn 2+ ,
Mg 2+ ), which is thought to form a complex with the phosphate moiety of cAMP,
a pocket containing an invariant glutamine (Q pocket), which forms hydrogen
bonds with the nucleotide (purine) moiety of cAMP, and a solvent pocket. PDE4
inhibitors occupy this active site through a number of important interactions and
prevent cAMP metabolism. These include indirect binding to the metal ions via the
formation of hydrogen bonding to water while hydrophobic interactions between
the planar ring structure of these inhibitors and hydrophobic amino acid residues
such as phenylalanine and isoleucine serve to “clamp” the inhibitor within the
active site. There are also hydrogen bond interactions between the aromatic ring
structure of these inhibitors and the invariant glutamine residue in the Q pocket, the
site which is normally occupied by the nucleotide moiety of cAMP (Xu et al. 2000 ;
Card et al. 2004 ; Wang et al. 2007 ).
There are considerable challenges to the synthesis of subtype selective
inhibitors due to the high degree of sequence and structural homology within
the catalytic domains of the PDE4 subtypes (Xu et al. 2000 ;Cardetal. 2004 ;