In March, 1998, Pfizer launched sildenafil (Viagra) for the treatment of erectile dysfunction. This move had an explosive effect on Pfizer's financial figures. More generally, this pharmaceutical milestone changed public awareness of erectile dysfunction and boosted basic research activity relating to improved understanding and treatment of this problem. Just over 4 years later LeadDiscovery has produced a state of the art analysis of sexual dysfunction. Despite the success of sildenafil, blockbuster opportunities still exist, both for improved treatment of erectile dysfunction using 2nd generation PDE5 inhibitors or molecules directed towards other pathophysiological targets, and for the treatment of the largely ignored area of female sexual dysfunction. Sildenafil was originally developed for the treatment of cardiovascular disorders until serendipity precipitated one of the most well known examples of indication-switching. This report analyzes both the science and the pharmaceutical activity surrounding male and female sexual dysfunction, focusing on other opportunities for indication-switching as well as novel pharmacological targets. In short this report will provide researchers and business development personnel with one of the most up to date and informative analyses of this blockbuster producing therapeutic area.

"Indication switching", or the redirecting of a drug or a pharmacological target from one disease to another is attractive because it can speed products towards the market for limited additional cost. The launch of sildenafil revolutionized the erectile dysfunction market overnight while at the same time offering one of the most well known examples of "indication switching". Originally developed as a cardiovascular drug Pfizer researchers discovered serendipitously that sildenafil, and PDE5 inhibition in general, was an effective treatment of erectile dysfunction. The consequent upsurge in sexual dysfunction research has resulted in an explosion of data describing the potential of both novel targets and more developed targets for this group of indications.

Sildenafil's indication switch meant that it became a blockbuster almost overnight, with sales reportedly totaling $1.5 billion in 2001. Despite the success of sildenafil and improvements that are expected with the development of second generation PDE5 inhibitors, this approach remains unsuitable for 30-50% of patients due to the severity of disease or due to contraindications. A sizable market therefore remains for the treatment of erectile dysfunction, however of greater commercial significance is perhaps the female sexual dysfunction market. According to the much quoted JAMA article published in 1999, more American women (43%; about 40 million) than men (31%) experience some form of sexual disorder. Female sexual dysfunction represents a family of conditions that have few pharmacologic therapies. Of interest and in contrast to males, the distribution of female dysfunctions is fairly even among women ranging from 18 to 59 years of age. Approximately 20% of women with female sexual dysfunction suffer arousal disorder characterized by either a failure of vaginal engorgement/lubrication or an altered appraisal of arousal, and it has been suggested that treatments of female arousal disorder represent a market of similar size to that of erectile dysfunction. Female arousal disorder and moderate to severe erectile dysfunction thus represent indications with blockbuster potential. Due to the similarities between the corpus cavernosum and the clitoris with respect to both structure and innervation, a number of pharmacological targets may be appropriate for both indications. This report overviews male and female sexual physiology and the pathophysiology of erectile dysfunction and female arousal disorder. Furthermore the report analyzes the development of a number of candidate pharmacological targets for these indications, specifically: smooth muscle modulators (Rho-A/Rho kinase), vasocongestive targets (eg the nitric oxide pathway; VIP and the prostaglandins), vasoconstrictive pathways (eg adrenoceptors; endothelin and angiotensin) and central mediators (dopamine; oxytocin; serotonin and melanocortin). One target singled out is the adrenoceptor pathway which offers a potential target both for the treatment of severe erectile dysfunction and female arousal disorder, and furthermore we single out one molecule in preclinical development, HMP12 that is worthy of further development. More generally the report also surveys molecules in development for both male and female sexual dysfunctions and identifies those companies active in the field both as developers and licensees of new technology. In order to identify the most current trends in sexual dysfunction therapeutics patent activity over the past year has been analyzed. This report therefore offers a state of the art review of candidate targets and places this information in the context of current pharmaceutical development. Considering the high level of pharmaceutical activity surrounding many of the candidates for treatment of sexual dysfunction and the blockbuster potential of these targets when developed for sexual dysfunction this report may be considered as being of interest for the pharmaceutical sector in general.