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ESSM Science

Asif MuneerSection Editor:
Asif Muneer
Clinical Fellow in Urology
Insitute of Urology
UCLH
London
e-mail: asif.muneer@uclh.nhs.uk


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

Premature ejaculation (PE) is a common male sexual dysfunction affecting 5-40% of sexually active men. Definitions for PE have been subjective and lack standardisation. This led to a more recent and objective definition of premature ejaculation which depends upon the intra-vaginal ejaculation latency time (IVELT). However sev¬eral cut-off points ranging from 1 to 7 minutes have been suggested by dif¬ferent studies. A recent study based on normative data suggested a cut off point of 60 seconds for definite PE and 60-90 seconds for probable PE. Understanding the physiology of ejaculation is essential in order develop targeted therapies for premature ejaculation. We present an overview of the theories of premature ejaculation.

Introduction

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.

 

Reference list

      (1)    Kalsi JS, Ralph DJ, Madge DJ, Kell PD, Cellek S. A comparative study of sildenafil, NCX-911 and BAY41-2272 on the anococcygeus muscle of diabetic rats. Int J Impot Res 2004 Dec;16(6):479-85.
      (2)    Ko FN, Wu CC, Kuo SC, Lee FY, Teng CM. YC-1, a novel activator of platelet guanylate cyclase. Blood 1994 Dec 15;84(12):4226-33.
      (3)    Mulsch A, Bauersachs J, Schafer A, Stasch JP, Kast R, Busse R. Effect of YC-1, an NO-independent, superoxide-sensitive stimulator of soluble guanylyl cyclase, on smooth muscle responsiveness to nitrovasodilators. Br J Pharmacol 1997 Feb;120(4):681-9.
      (4)    Friebe A, Koesling D. Mechanism of YC-1-induced activation of soluble guanylyl cyclase. Mol Pharmacol 1998 Jan;53(1):123-7.
      (5)    Friebe A, Mullershausen F, Smolenski A, Walter U, Schultz G, Koesling D. YC-1 potentiates nitric oxide- and carbon monoxide-induced cyclic GMP effects in human platelets. Mol Pharmacol 1998 Dec;54(6):962-7.
      (6)    Wohlfart P, Malinski T, Ruetten H, Schindler U, Linz W, Schoenafinger K, et al. Release of nitric oxide from endothelial cells stimulated by YC-1, an activator of soluble guanylyl cyclase. Br J Pharmacol 1999 Nov;128(6):1316-22.
      (7)    Stasch JP, Becker EM, onso-Alija C, Apeler H, Dembowsky K, Feurer A, et al. NO-independent regulatory site on soluble guanylate cyclase. Nature 2001 Mar 8;410(6825):212-5.
      (8)    Ko FN, Wu CC, Kuo SC, Lee FY, Teng CM. YC-1, a novel activator of platelet guanylate cyclase. Blood 1994 Dec 15;84(12):4226-33.
      (9)    Lee FY, Lien JC, Huang LJ, Huang TM, Tsai SC, Teng CM, et al. Synthesis of 1-benzyl-3-(5'-hydroxymethyl-2'-furyl)indazole analogues as novel antiplatelet agents. J Med Chem 2001 Oct 25;44(22):3746-9.
    (10)    Selwood DL, Brummell DG, Budworth J, Burtin GE, Campbell RO, Chana SS, et al. Synthesis and biological evaluation of novel pyrazoles and indazoles as activators of the nitric oxide receptor, soluble guanylate cyclase. J Med Chem 2001 Jan 4;44(1):78-93.
    (11)    Straub A, Stasch JP, onso-Alija C, et-Buchholz J, Ducke B, Feurer A, et al. NO-independent stimulators of soluble guanylate cyclase. Bioorg Med Chem Lett 2001 Mar 26;11(6):781-4.
    (12)    Kalsi JS, Rees RW, Hobbs AJ, Royle M, Kell PD, Ralph DJ, et al. BAY41-2272, a novel nitric oxide independent soluble guanylate cyclase activator, relaxes human and rabbit corpus cavernosum in vitro. J Urol 2003 Feb;169(2):761-6.
    (13)    Bischoff E, Schramm M, Straub A, Feurer A, Stasch JP. BAY 41-2272: a stimulator of soluble guanylyl cyclase induces nitric oxide-dependent penile erection in vivo. Urology 2003 Feb;61(2):464-7.
    (14)    Miller LN, Nakane M, Hsieh GC, Chang R, Kolasa T, Moreland RB, et al. A-350619: a novel activator of soluble guanylyl cyclase. Life Sci 2003 Jan 17;72(9):1015-25.
    (15)    Teixeira CE, Priviero FB, Webb RC. Effects of 5-cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]pyrim idin-4-ylamine (BAY 41-2272) on smooth muscle tone, soluble guanylyl cyclase activity, and NADPH oxidase activity/expression in corpus cavernosum from wild-type, neuronal, and endothelial nitric-oxide synthase null mice. J Pharmacol Exp Ther 2007 Sep;322(3):1093-102.
    (16)    Stasch JP, onso-Alija C, Apeler H, Dembowsky K, Feurer A, Minuth T, et al. Pharmacological actions of a novel NO-independent guanylyl cyclase stimulator, BAY 41-8543: in vitro studies. Br J Pharmacol 2002 Jan;135(2):333-43.
    (17)    Straub A, et-Buckholz J, Frode R, Kern A, Kohlsdorfer C, Schmitt P, et al. Metabolites of orally active NO-independent pyrazolopyridine stimulators of soluble guanylate cyclase. Bioorg Med Chem 2002 Jun;10(6):1711-7.
    (18)    Evgenov OV, Pacher P, Schmidt PM, Hasko G, Schmidt HH, Stasch JP. NO-independent stimulators and activators of soluble guanylate cyclase: discovery and therapeutic potential. Nat Rev Drug Discov 2006 Sep;5(9):755-68.
    (19)    Stasch JP, onso-Alija C, Apeler H, Dembowsky K, Feurer A, Minuth T, et al. Pharmacological actions of a novel NO-independent guanylyl cyclase stimulator, BAY 41-8543: in vitro studies. Br J Pharmacol 2002 Jan;135(2):333-43.
    (20)    Stasch JP, Becker EM, onso-Alija C, Apeler H, Dembowsky K, Feurer A, et al. NO-independent regulatory site on soluble guanylate cyclase. Nature 2001 Mar 8;410(6825):212-5.
    (21)    Stasch JP, onso-Alija C, Apeler H, Dembowsky K, Feurer A, Minuth T, et al. Pharmacological actions of a novel NO-independent guanylyl cyclase stimulator, BAY 41-8543: in vitro studies. Br J Pharmacol 2002 Jan;135(2):333-43.
    (22)    Schermuly RT, Stasch JP, Pullamsetti SS, Middendorff R, Muller D, Schluter KD, et al. Expression and function of soluble guanylate cyclase in pulmonary arterial hypertension. Eur Respir J 2008 Oct;32(4):881-91.
    (23)    Schermuly RT, Stasch JP, Pullamsetti SS, Middendorff R, Muller D, Schluter KD, et al. Expression and function of soluble guanylate cyclase in pulmonary arterial hypertension. Eur Respir J 2008 Oct;32(4):881-91.
    (24)    Grimminger F, Weimann G, Frey R, Voswinckel R, Thamm M, Bolkow D, et al. First acute haemodynamic study of soluble guanylate cyclase stimulator riociguat in pulmonary hypertension. Eur Respir J 2009 Apr;33(4):785-92.
    (25)    Frey R, Muck W, Unger S, rtmeier-Brandt U, Weimann G, Wensing G. Single-dose pharmacokinetics, pharmacodynamics, tolerability, and safety of the soluble guanylate cyclase stimulator BAY 63-2521: an ascending-dose study in healthy male volunteers. J Clin Pharmacol 2008 Aug;48(8):926-34.
    (26)    Stasch JP, Dembowsky K, Perzborn E, Stahl E, Schramm M. Cardiovascular actions of a novel NO-independent guanylyl cyclase stimulator, BAY 41-8543: in vivo studies. Br J Pharmacol 2002 Jan;135(2):344-55.
    (27)    Schindler U, Strobel H, Schonafinger K, Linz W, Lohn M, Martorana PA, et al. Biochemistry and pharmacology of novel anthranilic acid derivatives activating heme-oxidized soluble guanylyl cyclase. Mol Pharmacol 2006 Apr;69(4):1260-8.