The discovery of nitric oxide (NO) as one of the major effectors in penile erectile function has led to considerable research into corpus cavernosal physiology and it is now well accepted that NO produces relaxation of this muscle through the stimulation of guanylate cyclase and the consequent production of cGMP. This cyclic nucleotide is removed through the action of phosphodiesterases, principally PDE5. Hence a number of pharmacological approaches to the treatment of erectile dysfunction have centered on the use of NO donors, guanylate cylcase activators and PDE5 inhibitors (for a full review of current and emerging targets for erectile dysfunction Click here).

The clinical use of NO donors has generally produced disappointing results. For example, although SNP has been shown to be able to increase cGMP levels, the erectile effect of NO donors in the clinic has mostly been insufficient to support the development of this therapeutic class as a monotherapy. The development of PDE5 inhibitors has, in contrast been a resounding success. This is well exemplified by the commercial rewards reaped by Pfizer following their launch of sildenafil (Viagra). Despite the success of this drug, a large proportion of patients are either unresponsive to or, are unable to use sildenafil. Hence, blockbuster opportunities still exist for improved treatment of erectile dysfunction using either 2nd generation PDE5 inhibitors or molecules directed towards other pathophysiological targets

Bayer have been focusing on the development of molecules able to directly stimulate soluble guanylyl cyclase independently of NO. BAY 41-2272 is a novel non-NO-based direct stimulator of soluble guanylyl cyclase. BAY 41-2272 was administered to conscious rabbits intravenously (IV) and orally (PO) but only induced weak penile erections in conscious rabbits after IV (1 mg/kg) and PO (10 mg/kg) administration in the absence of an NO donor. However, the efficacy of BAY 41-2272 was potentiated by the simultaneous administration of SNP. Through simultaneous SNP administration, the effective doses of BAY 41-2272 were reduced significantly (minimal effective dose 0.1 mg/kg IV and 1 mg/kg PO). The results of this study clearly demonstrated the effect of BAY 41-2272 on penile erection in the conscious rabbit model after PO and IV administration. The time-course and onset of erection was concurrent with the stimulation by exogenous NO (SNP), suggesting that this new pharmacologic mechanism of soluble guanylyl cyclase stimulation could be used in the treatment of erectile dysfunction. Of key importance, because the effect is increased by SNP, it can be expected that BAY 41-2272 would have enhanced activity during sexual arousal, when NO is produced endogenously. This molecule is therefore expected to have many of the therapeutic effects of PDE5 inhibitors but without adverse effect related to the non-specific inhibition of other PDE subtypes.

Entry date March, 2003

Adapted from Bischoff et al, Urology 2003 Feb;61(2):464-7.

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