Chapter 1 Potential CNS Applications for Phosphodiesterase Enzyme Inhibitors

The interest in potential therapeutic utility of PDE inhibitors for CNS disorders is growing as evidenced by recent publications and presentations. There is an improved understanding of the roles played by second messengers cAMP and cGMP in signal transduction pathways thought to be linked with receptors and biochemical mechanisms associated with disease processes. Coupled with increasing evidence of genetic linkages between PDEs and CNS disorders, this research has provided the basic groundwork for investigation of PDEs as CNS drug targets. There are a variety of structural classes of compounds that are active against each phosphodiesterase, and evidence suggests that selective inhibitors of PDEs can be identified. The structural diversity of PDE inhibitors provides a multitude of opportunities for development of compounds with drug-like properties. Furthermore, phosphodiesterase inhibition, which avoids direct interaction of a compound with a cell surface or nuclear receptor, may circumvent some of the target selectivity issues that can complicate receptor-based therapeutic approaches. As noted above, the specific subcellular distribution of phosphodiesterase enzymes is a key feature of their ability to modulate intracellular signaling pathways. This localization of the enzyme may minimize non-specific target interactions. However, one potentially challenging feature in PDE inhibitor development is the prerequisite for a chemical series that demonstrates efficacy in a cellular model. The availability of cell-based assays reflective of inhibition of selective PDE enzymes is currently limited, and improved methods will be of significant value to the field. The availability of X-ray crystal structures of PDEs with inhibitors bound will no doubt aid the rational design of more potent derivatives. Preclinical validation of PDE2, 4, 9, and 10 as targets for important disorders including schizophrenia, depression, anxiety, and cognition has been achieved. The animal models employed in these screens are predictive of the potential for efficacy in humans. At this writing, the only PDE inhibitor known to be in human clinical studies for a CNS indication is the PDE4 inhibitor MEM1414 for Alzheimer's disease. If the surge of interest in the field is a preview of the potential of the area, investigators can look forward to the discovery of PDE inhibitors that will attempt to provide human clinical validation for a range of diseases for which new treatment mechanisms are a well-recognized medical need.