Editorial [ Hot Topic : Viagra's Cousins - Towards a New Generation of Phosphodiesterase Inhibitors (Guest Editor: Philip Thompson) ]

In this issue of Current Topics in Medicinal Chemistry, four review articles have been compiled to exemplify the state-ofthe- art in the design and application of phosphodiesterase inhibitors. This is not a new topic; for fifty years chemists have been called upon to provide novel compounds that inhibit this family of enzymes and it has been these compounds, in league with advances in cellular and molecular biology that have helped unravel the complexities of the cyclic nucleotide second messenger systems. In the last decade however, one advance has thrust this research area back to the forefront of contemporary drug design - the successful clinical application of sildenafil (Viagra) as a medication for male erectile dysfunction (MED). The commercial and clinical success of Viagra, a PDE5 inhibitor and its PDE5 inhibiting competitors, vardenafil and tadalafil, essentially won the argument that PDE inhibitors could be successful modern drugs, and thus provided the evidential weight to push PDE-based research proposals into fruition in industry and academia alike. Of course, PDE5 is but one isoform of this enzyme family, which continues to grow with gene splicing variants emerging across the various pharmacologically and genomically defined family of 11 members including over 60 sub-types. Significant drug discovery efforts have resulted in a number of current clinical candidates against PDE4-related diseases, and significant research efforts against other isoforms. Overall though, the capacity to identify PDE isoforms currently outstrips our ability to characterise their roles in physiology or pathology, and the state of knowledge regarding many of the PDE isoforms is superficial or controversial. This brings us to something of a Catch 22 in respect of advance in the PDE field. Typically, medicinal chemistry campaigns are not undertaken without some observation of a therapeutic potential relating to a selected biological target. However, in the case of the majority of PDEs, such therapeutic potential still is some distance short of validation. This is mainly due to the lack of pharmacological inhibitors. It is thus down to the groups with the curiosity and opportunity to look, not just for drugs but for the crucial reagents which will fuel discovery biology in what is a fundamental component of the circuitry of the cell. In deference to the most significant recent technological breakthroughs, the articles show the powerful application of x-ray crystallography as a tool for drug discovery. Hengming Ke, who was the first to describe the crystal structure of the catalytic domain PDE4, together with Huanchen Wang surveys the burgeoning crystal data released since 2000, to explore what that information tell us about the origins of substrate specificity and inhibitor selectivity across PDE classes. Another contribution comes from the laboratories where Viagra was developed at Pfizer in Sandwich, UK. Michael Palmer, Andrew Bell, David Fox and David Brown show the power of high throughput crystallography and screening, in accelerating the hit to lead process for discovery of second generation PDE5 inhibitors. A pharmacological perspective on PDE5 beyond MED is provided by Bing Zhu and Samuel Strada, from University of Sth. Alabama, who have examined the role of that enzyme together with other cGMP-hydrolyzing isoforms in diseases such as cancer with the clinical candidate, Exisulind and its analogues. They also explore the return of PDE5 inhibition to its “first home” in the study of pulmonary hypertension, and describe the discoveries that are validating PDE5 inhibition as a target in this therapeutic area. Finally, Eva Degerman, Vince Manganiello and I have turned our attention to the need for new PDE3 inhibitors as pharmacological tools and potential therapeutics. An area largely neglected, since the 1990's on the back of clinical failures, the advances in molecular biology, structural biology and cell physiology demand revived activity in the area. We attempt to distill the mass of medicinal chemistry from the 1980's and 1990's to discover new opportunities in the field, particularly with respect to PDE3 sub-types, PDE3A and PDE3B. Necessarily, these articles are limited to reviewing a small subset of the range of isoforms of current and future interest. Inhibitors of those less famous isoforms such as PDE2, PDE7 and PDE9 are emerging regularly in the patent and peer-reviewed literature and it seems likely that there maybe a real prospect of having available isoform-selective inhibitors at PDEs 1 - 11, and many that can distinguish between sub-types. Hopefully however, there is something to be retrieved in each review for researchers in the field of PDE inhibition that might inspire a worthwhile experiment. I thank Dr. Allen Reitz for the invitation to prepare this collection; it is humbling to present the offerings of a number of major players in the field of PDE research and I thank them for their willingness to participate and embrace the themes of this issue. Their conceptual and technical approaches are certainly those that will advance research in the PDE field.