Sexual Medicine Presentations

Premature Ejaculation

Novel therapies for ED – Soluble Guanylate Cyclase (sGC) activators

Jas Kalsi, BSc(Hons), FRCS(Urol), Post CCT Fellow in Andrology
Asif Muneer, MD, FRCS(Urol), Consultant Uro-Andrologist
Suks Minhas, MD, FRCS(Urol), Consultant Uro-Andrologist

Despite major advances in the understanding of the physiology of penile erection and the pathophysiology of erectile dysfunction (ED), it remains a significant global male health problem. The PDE5 inhibitors, sildenafil (Viagra; Pfizer), tadalafil (Cialis; Lilly), and vardenafil (Levitra; Bayer) have revolutionalised the treatment of ED. However, up to 30% of patients fail to respond including long-term diabetics. It is known that Nitric Oxide (NO) release from nitrergic nerves is impaired in patients with diabetes, giving rise to diabetes-induced erectile dysfunction.

Rats with diabetes induced by streptozotocin have been shown to have reduced nitrergic relaxation responses (1). Therefore, new therapeutic targets that may relax cavernous smooth muscle without the need for endogenous NO are needed. One such approach is NO independent activation of soluble guanylate cyclase.

Soluble Guanylate Cyclase Activators
In 1994, an indazole derivative YC-1 (2), was characterized as an NO-independent, haem-dependent stimulator of highly purified sGC (3). It stimulated sGC directly and sensitizes the enzyme towards its native activator NO (4). However, it acted as a non-specific phosphodiesterase inhibitor (5) and stimulated the synthesis and release of NO (6).

Following a chemical optimization programme BAYER discovered a pyrazolopyridine derivative BAY41-2272 by using a photoaffinity label on the purified enzyme (7). The sGC activators can now be divided into those which are NO-independent but haem-dependent stimulators and those which are NO- and haem-independent.

Haem-dependent sGC stimulators
After the discovery of YC-1 (8), other compounds which activate sGC in an NO-independent fashion have been identified (9-11) including BAY41–2272, CMF-1571 and A-350619. In-vitro studies demonstrate that they are all haem-dependent sGC-stimulators as they share a crucial dependency on the presence of the reduced prosthetic haem moiety and strong synergistic enzyme activation when combined with NO (12). Further studies have shown that BAY 41-2272, but not the PDE5 inhibitor sildenafil, enhances residual nitrergic relaxation responses in the anococcygeus muscle of streptozotocin diabetic rats. This suggests that NO-independent sGC stimulation may have greater efficacy than PDE-5 inhibition in the treatment of patients with diabetes-induced erectile dysfunction (1). NO-independent sGC stimulators have also been shown to act in synergy with the NO donor, sodium nitroprusside, to produce penile erection in rabbits, implying that these compounds will enhance the response to endogenous NO released during sexual stimulation and thus facilitate a natural penile erection (13;14). Recent data suggest that BAY 41-2272 may also reduce superoxide formation and NADPH oxidase expression in the corpus cavernosum (15), thereby increasing the bioavailability of NO.

Two further pyrazolopyridine derivatives have now been identified , BAY 41-8543 (16;17) and BAY 63-2521 (18;19). They have been shown to have an improved potency and specificity for sGC. It has been proposed that in the absence of NO, BAY 41-2272 stimulates sGC activity approximately 20-fold from baseline (20) whereas BAY 41-8543 and BAY 63-2521 exhibit even greater potency stimulating sGC activity up to 70-90fold (21) (22). BAY 63-2521 promotes vasorelaxation in arteries isolated from nitrate-tolerant rabbits, and decreases acute pulmonary vasoconstriction in isolated mouse lungs(23).  This compound has now undergone phase 1 and proof-of-concept clinical trials (24;25), and phase 2 trials are currently in progress.

Haem-independent sGC activators
Using a rapid and highly sensitive cell-based assay for cGMP as a screening tool, BAY58–2667 was identified to be the first haem-independent NO-independent activator of sGC in 2002. The activation of sGC by this compound was even stronger after oxidation or removal of the prosthetic haem group, indicating a previously unknown mechanism of enzyme activation (26).

Other compounds with comparable characteristics include the anthranilic acid derivatives HMR1766 and S3448. Both compounds have been shown to activate sGC preparations in a concentration-dependent manner and act synergistically with NO donors. However, instead of being inhibited, they were found to be potentiated by the haem-iron oxidant ODQ. Moreover, in anesthetized pigs, an intravenous HMR1766 injection has been demonstrated to result in a decrease in arterial blood pressure. (27). The potential importance of these new drugs is that they target a modified state of sGC that is present in both animals models and in human disease states.

Conclusion
Soluble guanylate cyclase activators are currently in trials for the management of pulmonary hypertension. The development of newer and more selective compounds may in the future allow them to be used more selectively in the management of ED. This would have significant potential advantages for patients with NO dysfunction such as long-term diabetics who at the moment often fail medical treatment. Clinical trials with these agents are required to assess their efficacy and safety in humans.