Phosphodiesterase Inhibitors: Factors That Influence Potency, Selectivity, and Action - Phosphodiesterases as Drug Targets - page 48

Abstract Cyclic nucleotide phosphodiesterases (PDEs) are promising targets for
pharmacological intervention. The presence of multiple PDE genes, diversity of the
isoforms produced from each gene, selective tissue and cellular expression of the
isoforms, compartmentation within cells, and an array of conformations of PDE
proteins are some of the properties that challenge the development of drugs that
target these enzymes. Nevertheless, many of the characteristics of PDEs are also
viewed as unique opportunities to increase specificity and selectivity when design-
ing novel compounds for certain therapeutic indications. This chapter provides
a summary of the major concepts related to the design and use of PDE inhibitors.
The overall structure and properties of the catalytic domain and conformations
of PDEs are summarized in light of the most recent X-ray crystal structures. The
distinctive properties of catalytic domains of different families as well as the
technical challenges associated with probing PDE properties and their interactions
with small molecules are discussed. The effect of posttranslational modifications
and protein-protein interactions are additional factors to be considered when
designing PDE inhibitors. PDE inhibitor interaction with other proteins needs to
be taken into account and is also discussed.

Keywords Compartmentation Cyclic AMP Cyclic GMP PDE1 PDE2 PDE3

PDE4 PDE5 PDE6 PDE7 PDE8 PDE9 PDE10 PDE11 Phosphodiesterase

Phosphodiesterase inhibitors

1 PDE Superfamily

The mammalian superfamily of cyclic nucleotide (cN) phosphodiesterases (PDEs) is
remarkably complex. It comprises 11 distinct families (PDEs 1-11) with protein
products derived from 21 genes (Bender and Beavo 2006 ; Conti and Beavo 2007 );
some families are encoded by a single gene, whereas others are products of multiple
genes, but there are alternative splice variants of the gene products in all the families
except for PDE6. In several instances, multiple promoters that are differentially
regulated influence expression of the PDE mRNA transcripts (Bender and Beavo
2006 ; Conti and Beavo 2007 ; Omori and Kotera 2007 ), and extensive alternative
splicing of the mRNAs produces a vast array of protein products. It is now estimated
that there are close to 100 different protein products of these genes, and these are
distinguished by having different regulatory features, catalytic characteristics, tissue
distributions, subcellular localizations, targeting to signaling complexes and sensi-
tivities to PDE inhibitors (Fig. 1 ). The need for such a large array of PDE isoforms in
controlling cN levels and maintaining appropriate cellular functions is still poorly
understood. PDEs are typically in low abundance in cells but may be highly
expressed in particular tissues or regions of cells for regulation of specific physio-
logical effects (Castro et al. 2006 ; Cote 2006 ; Houslay 2010 ; Juilfs et al. 1997 ;
MacFarland et al. 1991 ). Most cells contain multiple PDEs that have overlapping
specificities and affinities for cAMP or cGMP. However, where studied, it seems
clear that while there may be some degree of redundancy in function, each of the
PDEs provides important regulatory control of cNs in a particular cell or region of