Send Orders for Reprints to [email protected] Recent Patents on CNS Drug Discovery, 2014, 9, 41-53 41 Recent Advances in the Treatment of Neurogenic Erectile Dysfunction

Rocco S. Calabrò*, Giovanni Polimeni and Placido Bramanti

IRCCS Centro Neurolesi “Bonino-Pulejo”, Messina, Italy

Received: November 19, 2013; Revised: December 14, 2013; Accepted: January 17, 2014 Abstract: Neurogenic erectile dysfunction (ED) can be broadly defined as an inability to sustain or maintain a penile erection owing to a neurological impairment, either centrally or peripherally or both. Although significant advances in the pharmacological treatment of ED have occurred in recent years, especially after the introduction of oral selective phos- phodiesterase type 5 inhibitor, the treatment of neurological patients with ED may be challenging for prescribers, given poor data available on this topic and the variety of etiologic factors (iatrogenic, endocrine, psychiatric and psychosocial) to consider. At the same time, several, new oral, local and surgical treatments are available and their efficacy and safety depend on the specific cases. This review provides a comprehensive and updated description of current and future ED therapies, including assigned patents, with a special focus on the treatment of neurogenic erectile dysfunction. Keywords: Dopaminergic agonists, guanylate-cyclase activators, melanocortins, neurogenic erectile dysfunction, patents, PDEi, potassium channel inhibitors.

INTRODUCTION increase with the possible direct activation of myosin via Rho-kinase [1]. Neurophysiology of Erectile Function: A Brief Overview The penis receives innervation from sacral parasympa- Erection is a neurovascular event characterized by the thetic (pelvic, S2-S4), thoracolumbar sympathetic (T10-L2; tumescence of the cavernous bodies that relies upon integra- hypogastric and lumbar chain) and somatic (pudendal) tion of neural and humoral mechanisms at various levels of nerves, with the major excitatory input to the penis being the nervous system. It requires the participation of auto- provided by the parasympathetic nervous system, responsi- nomic and somatic nerves and the integration of numerous ble for vasodilatation of the penile vasculature and erection, spinal and supraspinal sites. whereas sympathetic nervous system seems to play a pivotal Vasodilatation is the first event in the development of role in the detumescence of the penis [4]. Erections occur in erection, depending on endocrine, paracrine and maybe response to tactile, visual, imaginative and olfactory inputs autocrine mechanisms, and it is the direct consequence of the and are triggered by supraspinal centers. It is likely that re- increase of blood flow and pressure into lacunar space [1]. flexogenic and psychogenic stimuli act synergistically via Endothelium-dependent relaxation of the corpus cavernosum sacral parasympathetic route [5]. In addition, hypothalamic is mediated only by nitric oxide (NO), while penile arteries (> MPOA) and limbic pathways are thought to play a central dilatation is due both to NO and to endothelium-derived hy- role in erection. Many other supraspinal centers (i.e. dor- perpolarizing factor (EDHF) [2]. Once produced, NO dif- somedial and ventromedial and paraventricular hypothalamic fuses into the vascular smooth muscle cells adjacent to the nuclei, Barrington’s nucleus of the pons, medullary raphe, endothelium where it binds and activates guanylyl cyclase, nPGi, locus ceruleus and periaqueductal gray) and their leading to cyclic guanosine monophosphate (cGMP), which connections with limbic and cortical areas are involved in serves as a second messenger for many important cellular erection [6]. functions, particularly for signaling smooth muscle relaxa- tion [3]. Erectile Dysfunction in Neurological Disorders Detumescence of the penis is mediated by adrenergic Neurogenic erectile dysfunction (ED) can be broadly nerve terminals whose neurotransmitter, noradranaline, acti- defined as an inability to sustain or maintain a penile erec- vates adrenergic receptors. Moreover, endothelin-1, a potent tion owing to a neurological impairment, either centrally or vasoconstrictor peptide is involved in the regulation of con- peripherally or both. tractility of the human cavernous tissue. Finally, when the penile smooth muscle is activated, various signaling mecha- Epilepsy nisms lead to an intracellular free calcium concentrations Sexual dysfunction (SD) due to epilepsy can be directly related to seizures (ictal), or unrelated in time to seizures *Address correspondence to this author at the Neurorehabilitation Unit, occurrence (interictal). Although its etiology remains still IRCCS Centro Neurolesi “Bonino Pulejo”, via Palermo, S.S. 113, C.da unknown, it is likely to be multifactorial, involving neuro- Casazza, 98124 Messina, Italy; Tel: +39-090-60128840; Fax: +39-090- 60128850; E-mail: [email protected] logical, iatrogenic, endocrine, psychiatric and psychosocial factors [7]. The prevalence of ED in individuals with epi-

2212-3954/14 $100 00+ 00 © 2014 Bentham Science Publishers 42 Recent Patents on CNS Drug Discovery, 2014, Vol. 9, No. 1 Calabrò et al. lepsy ranges from 3% in outpatients to 58% in patients the phosphodiesterase 5 (PDE5), an enzyme which is present evaluated for epilepsy surgery [8]. in high concentrations in the smooth muscle of the corpus cavernosum, hydrolysing cGMP, that leads to relaxation of Multiple Sclerosis the corpus cavernosum and penile erection [18]. Two other PDEIs, tadalafil and vardenafil, have subsequently joined Multiple sclerosis (MS) is the most common cause of sildenafil in the ED market [18], although more recently sev- neurological disability among young adults, affecting about eral other molecules have been marketed and/or approved in 2.5 million people around the world. The prevalence of SD is some countries (i.e. avanafil, udenafil, lodenafil and mirode- significantly higher in patients with MS than in the general nafil). population, with ED being reported in 50-75% of cases [9]. Although all PDEIs share a common mechanism of ac- SD in MS patients can be divided into primary (directly tion, dissimilarities exist regarding their pharmacokinetic due to MS-related neurological deficits), secondary attrib- and selectivity for the PDE enzymes [19-26]. uted to MS-related physical impairments and symptoms or drugs used for MS treatment), and tertiary SD (due to psy- PDEIs have limited contraindications, including con- chological, social and cultural problems) [10]. comitant use of nitrates, patients with a history of retinitis pigmentosa or diseases predisposing to priapism such as leu- Spinal Cord Injury kemia or multiple myeloma. Moreover, attention should be paid to those patients who showed hemodynamic instability Spinal cord injury (SCI) in men results in defects in erec- while receiving -blockers alone, since they are at increased tile and ejaculatory function, and male reproductive poten- risk of symptomatic hypotension with concomitant use of tial. After a complete, high lesion, psychogenic erections are PDEIs. Common adverse events with all PDEIs include lost whereas reflex erection remains intact; low lesions, in- headache, flushing, nasal congestion and dyspepsia. Specific deed, substantially reduce erectile capacity [11]. drug-related adverse effects include visual disturbance, mainly for sildenafil and vardenafil [19], and myalgia/back Stroke pain, mainly for tadalafil [20]. Moreover, the possible causal relationship between non-arteritic anterior ischemic optic A decline in libido, erection and ejaculation are frequent neuropathy (NAION) and PDEIs use has raised important in men suffering from stroke, with a reported prevalence of post-stroke ED that varies from 17% to 42% [12]. The cause concerns [21]. of ED in post-stroke patients is often multifactorial, with a Several studies have been published exploring the effi- complex interplay between psychological and organic fac- cacy and safety of PDE5Is in patients with different neuro- tors. Some authors have postulated a relationship between logical disorders such as SCI and MS. the location of the lesion and sexual change, since ED seems Tadalafil has shown promise in minimizing ED and in- to be more frequent when the right hemisphere is involved creasing QoL for men with MS [27]. Nevertheless, a recent [13]. Cochrane Systematic review assessing the efficacy and safety of sildenafil citrate for ED in patients with MS con- Parkinson’s Disease cluded that evidences supporting the efficacy of sildenafil Despite physical and cognitive impairments after Parkin- citrate in patients with MS are limited, and further, well de- son’s disease (PD) have been well studied [14], little is signed RCT are needed [28]. known about SD, occurring in about 60% of men with PD A recent study by Lombardi et al. [29] showed that silde- and greatly affecting their quality of life. ED may arise either nafil is efficient and well-tolerated in the long term treatment from the neurodegenerative processes of PD or from several (i.e. 10-year-follow-up) for ED caused by SCI. In clinical other disease-related factors, including the psychosocial trials, PDEIs were effective in 85% of SCI patients on silde- stress, burden of chronic illness, fatigue, difficulty in fine nafil, 74% of the patients on vardenafil and 72% of the pa- finger movements, and lowered self-esteem associated. tients on tadalafil [30]. The mean duration of erection was 34, 28 and 26 min, respectively. Adverse effects were mild, Neuropathy and usually attenuated with continued dosing. More than Diabetic neuropathy, as well as other peripheral neuropa- 70% of the patients on vardenafil and tadalafil required thies, including those following radical prostatectomy, may higher doses of 20 mg, whereas 50 mg of sildenafil was ef- also cause ED affecting small myelinated and unmyelinated fective in 55% of the patients. nerve fibers [15-17]. As far as the influence of PDEIs for ED in men with epi- lepsy is concerned, a recent review suggested a possible pro- PHARMACOLOGICAL TREATMENT OF NEURO- convulsant effect of these drugs [31]. Thus, healthcare pro- GENIC ED fessionals should therefore be aware of the possible influ- ence of PDEIs on seizure susceptibility. Oral Pharmacotherapy Sildenafil citrate (50 mg) was more effective in improv- Phosphodiesterase 5 Inhibitors (PDEIs). The introduc- ing erection in men with PD than in individuals with parkin- tion of sildenafil in 1998 can be considered the watershed in sonisms [32]. However, researchers have suggested supine the pharmacological treatment of ED, because of its broad and standing blood pressure measurements before prescrib- efficacy for different types of ED and its ease of use. Silde- ing sildenafil citrate to patients with PD to avoid severe nafil is a potent and selective inhibitor of the catalytic site of iatrogenic hypotension [33]. Treatments of Neurogenic ED Recent Patents on CNS Drug Discovery, 2014, Vol. 9, No. 1 43

Although generalized tonic-clonic seizures have been morphine injections have been used for ED in individuals reported in patients taking sildenafil who had no history of without PD. As in men with PD apomorphine has been re- epilepsy [34], the drug can be used safely in epilepsy pa- ported to cause penile erections and hypersexuality [45, 46], tients for restoring sexual performance. the drug could be investigated for ED in this neurodegenera- Interestingly, when pelvic autonomic innervation is tive disorder. bilaterally disrupted after prostatectomy, PDEIs can have no Naltrexone. Assuming that endogenous opioids may be benefit as their action depends on some neural integrity to involved in sexual dysfunction, it has been shown that supply a minimum of nitric oxide neurotransmitter. Thus, the naltrexone, an opiod antagonist, increased the frequency of nerve-sparing surgical techniques are promising, and, in morning erection and successful coital attempts [47, 48]. these patients, PDEIs are considered as the first line treat- Trazodone. Trazodone is an atypical antidepressant drug, ment to restore spontaneous erectile function [35, 36]. which selectively inhibits central 5HT uptake and increases Of particular recent interest is the utilization of PDEIs as the turnover of brain dopamine. Although its use in the routinely dose medication since daily PDEIs may help to treatment of ED is still controversial, some pilot studies gave prevent apoptosis in the corporal sinusoids, preserve smooth promising results either in the treatment of individuals with muscle content, and reduce collagen accumulation in a vari- ED [49] or with selective serotonin-reuptake inhibitor- ety of disease states. A RCT on 194 individuals with ED and induced SD [50]; furthermore, a combination of trazodone a review comparing tadalafil given once-daily in low doses with sildenafil was effective to restore erectile function of with traditional dosing schedule (20 mg as needed), showed men with ED and a degree of psychogenic component [51]. that once daily 5 mg tadalafil is a valid alternative to on- Dietary supplements. Many dietary supplements and demand treatment in terms of both efficacy and tolerability nutriceuticals worldwide used not only have purported bene- [37]. However, in the absence of a large study demonstrating fits on erectile function, but also on the cardiovascular sys- clear long-term benefit from daily use of PDEIs for penile tem in general [52]. L-arginine is a NO donor for neural and rehabilitation, this type of therapy should still be considered endothelial NO-synthase increasing NO production when investigational [38]. consumed in supraphysiologic doses of more than 3 g per A variety of new PDEIs with promising pharmacokinetic day [53]. To boost NO levels, L-arginine is often combined properties are in development for the management of ED in with the NO-synthase stimulant pygnogenol, a pine bark humans, as better specified elsewhere. derivative, and this combined approach seems to be effective even in human ED. Recently, L-arginine was also tested in Patients with severe neurological damage, post-radical combination with adenosine monophosphate in 26 patients prostatectomy or severe vascular disease may not respond to with mild-to-moderate ED [54]; this pilot phase II study PDEIs, probably due to a decreased expression or activity of showed that the on-demand oral administration at a high neural or endothelium NO synthase. dosage of L-arginine aspartate plus adenosine monophos- When novel dosing strategies are not effective in opti- phate may be effective and well tolerated, although larger mizing the efficacy of PDEIs in these specific cases, other studies are needed. treatment options should be considered. Although Ginkgo biloba has been used more frequently Phentolamine. Phentolamine induces relaxation of cor- to improve cerebrovascular microcirculation, its central ef- pus cavernosum erectile tissue mainly by blocking both 1 fect have been postulated to ameliorate iatrogenic ED. Cohen and 2 adrenergic receptors [39]. To date, its effectiveness AJ invented a method for treating such SD administering an and safety in ED management, at an oral dose of 40-80 mg, effective amount of Ginkgo extract (120 to 240 mg/ daily) has been suggested in limited studies [40]. [55]. Among different varieties of Ginseng which are fre- Yohimbine. Yohimbine facilitates erection by blocking quently found in dietary supplements, Korean Ginseng has been most extensively studied in relation to ED, with contro- central 2 adrenergic receptors and produces an increase in sympathetic drive and firing rate of neurons within the brain versial results. However, a recent multicenter, randomized, noradrenergic nuclei. The drug (up to 6 mg) seems to be su- double-blind, placebo-controlled study evaluating the effi- perior to placebo in the treatment of ED, although, overall, cacy of standardized Korean ginseng berry extract (SKGB) available results on treatment are not impressive [41, 42]. in 119 men with ED showed significant improvements on erectile function, ejaculation and other aspects of sexual We have to underline that adrenergic centrally acting function [56]. Finally, an improvement of erectile function agents are less indicated in ED secondary to neurological has been described with L-carnitine [57, 58], which acts disorders, especially when spinal or local neurogenic path- through a prostaglandin-induced vasorelaxation of arterioles, ways are disrupted. Thus, considering also the common ad- and with a combination of Propionyl-L-carnitine, L-arginine verse effects, their use is restricted to specific clinical condi- and niacin [59], although larger studies are needed. tions. Apomorphine. Apomorphine is a non selective D1/D2 Local Therapies receptor agonist with moderate efficacy and good tolerability Injectable and intraurethral agents are considered to sec- in the treatment of mild ED [43]. Apomorphine may be in- ond line therapy after the appearance of the effective oral jected subcutaneously or sublingually assumed; the latter PDEIs. However, the local delivery of medication remains formulation (2 and 3 mg) has recently been approved for useful, as in about 25-30% of ED patients PDE5i are ineffec- clinical use in several countries [44]. However, apomorphine tive [23, 60]. High discontinuation rates and a risk of priap- shows lower efficacy and tolerability than sildenafil. Apo- 44 Recent Patents on CNS Drug Discovery, 2014, Vol. 9, No. 1 Calabrò et al. ism represent the two most important limitations of this spaces. Efficacy rates (i.e. erection satisfactory for inter- treatment option [61]. course) as high as 90% have been described regardless of ED etiology [74, 75]. Papaverine. Papaverine is an opium alkaloid acting as a non specific PDEi with an increase in intracellular cAMP Constrictive ring. The constrictive ring is likely to be the and cGMP leading smooth muscle relaxation [62]. Intracav- only external device needed for management of ED in pa- ernosal papaverine injection was the first clinically effective tients with mild to moderate venous leakage and no coexist- pharmacological therapy for ED, producing a full erection in ing significant arterial insufficiency. about 35-55% of patients, depending on dose used (from 3 mg to more than 100 mg) and the underlying pathology [63]. Surgical Treatment PGE1 (alprostadil). Alprostadil is a potent synthetic The majority of vascular ED patients have pathological vasodilator and smooth muscle relaxant in man, chemically changes in the small vessels of the penis and, generally,  identical to the naturally occurring PGE1. It also has an 2 revascularization for such smaller arteries is challenging adrenergic blocking effect and hence has the potential of with long-term patients’ dissatisfaction and complications reducing sympathetic overtone in patients with psychogenic including pain, altered sensation, shortening of penile length ED. Intracavernosal injection of PGE1 is a second-line and glans hyperemia [75-78]. Also the long-term success treatment for ED in patients for whom therapy with PDEIs rate of penile vein ligation is poor [79]. Penile prosthesis has failed or is contraindicated; its efficacy was demon- offers a therapeutic alternative for patients who fail strated in several clinical trials where the rate of responders vasoactive drugs and vacuum-constrictive devices and who ranged from 40 to 70% [64, 65]. Intraurethral alprostadil are not candidates for vascular reconstruction procedures may also be a valid option in men having undergone prior [80-82]. radical retropubic prostatectomy [66]. The most common It has been demonstrated that the insertion of malleable adverse event is penile pain, while prolonged erection occurs penile prostheses in patients with SCI is associated with low in about 5% of the patients. complication rates and good patient satisfaction, and it may therefore represent an attractive option [83, 84]. Vasoactive Intestinal Polypeptide and Phentolamine. Vasoactive intestinal peptide (VIP) is a neurotransmitter The development of microsurgical techniques and free with regulatory actions on blood flow, secretion and muscle tissue transfers hold to promise of success for phallic rein- tone. VIPergic nerves are most densely concentrated in the nervation, whereas the major sensory nerve of the donor free penis around the pudendal arteries and in the erectile tissue flap is generally coapted to the pudendal nerve [85]. of the corpus cavernosum. VIP has been shown to elevate cAMP intracellular concentrations without affecting cGMP Future Treatments levels. Interestingly VIP given intracavernously is unable to Although currently available medications have dramati- induce erection on injection in potent men even in a high cally improved ED treatment, many patients still do not dose; however, when used in combination with phentolamine benefit from existing pharmacological options, because of or papaverine, it showed effective and safe [67]. Most com- their side effects, which may represent a major reason for monly reported adverse effects were facial flushing and discontinuation [86, 87], or due to their limited effectiveness headache. The combination of VIP and phentolamine is cur- in treating ED related to diabetes mellitus, prostatectomy or rently approved for treatment of ED in the United Kingdom, ageing, with only 40% to 65% of these cases benefiting from Denmark, and New Zealand. PDE5i therapy [88, 89]. Thus, the development of alternative Combinations. Phentolamine, papaverine, PGE1, and agents and/or approaches for the treatment of ED is needed. VIP are the vasoactive agents most commonly used in com- bination therapy of ED. This treatment is not only more ef- Peripherally Acting Compounds fective (also in SCI individuals) as a result of well-planned Novel PDE5Is strategies but it is also associated with a reduction in inci- dence of side effects and cost per dose [68, 69]. Chancellor Selective inhibition of PDE5 remains a mainstay in the et al. [70] showed that vacuum-pump devices were as effec- treatment of ED patients. Thus, efforts are underway to de- tive as papaverine injections in 18 males with SCI. velop and test new PDEIs, in order to obtain molecules with improved potency, tolerability or more convenient dosage Medicated Urethral System for Erection (MUSE) is a schedules [90, 91]. licensed alternative way to deliver alprostadil to corporal bodies [71-73]. SLx-2101 SLx-2101 (Surface Logic, Inc.) is an oral, selective, NON-PHARMACOLOGICAL TREATMENT OF SE- fast-onset, PDE5I which exhibits excellent potency in both VERE NEUROGENIC ED ex vivo and in vivo experiments and a long-lasting duration Non Surgical Devices (at least 36 – 48 h at all doses studied) [92]. The active metabolite SLx-2081 is responsible for this extended Vacuum constriction device. The device usually consists duration of the PDE inhibition [93]. Three phase 1 clinical of a wide clear plastic barrel that is placed around the penis studies with SLx-2101 have already been carried out with and sealed against the pubic region, providing a passive en- positive results in terms of safety, tolerability, dose gorgement of the penile tissue through the generation of an response and efficacy [93]. increasing negative pressure in the cavernous sinusoidal Treatments of Neurogenic ED Recent Patents on CNS Drug Discovery, 2014, Vol. 9, No. 1 45

In particular a double-blind, randomized, placebo- in IIEF-EF domain score in the group receiving 50 and 100 controlled phase I trial with single oral doses of SLx-2101 mg of mirodenafil, respectively, versus a 3.4 point increase (from 5 to 80 mg) in 40 healthy male volunteers, showed a in the placebo group [109]. More recently, a multicenter, clinically meaningful erectile positive effect on penile rigid- double-blind, placebo controlled trial evaluating the im- ity at doses of 20, 40, and 80mg [94], with few side provement in ED and lower urinary tract symptoms as well effects. as the safety of once daily administration of 50 mg mirode- nafil confirmed its efficacy and tolerability in 180 men with Avanafil ED [110]. Due to the modification in its structure, mirode- Avanafil (TA-1790, Vivus®, Inc.) is a pyrimidine deriva- nafil has got a 10-fold higher PDE5 selectivity than silde- tive recently approved by the US Food and Drug Admini- nafil [111, 112]. Pharmacokinetic data showed a shorter half- stration in three different dosages: 50 mg, 100 mg, or 200 life than the other currently available PDE5Is [113], with this mg. This agent exhibits a high selectivity for PDE5 [95], property representing an advantage in terms of lower inci- rapid absorption and a short half-life, with a Tmax of about dence of common side effects [114, 115]. 35 min and a t of 60 - 90 min, accounting as the fastest- Lodenafil Carbonate acting PDE5 inhibitor [96]. The novel PDE5i Lodenafil carbonate is a dimer acting Overall, avanafil was studied in over 1,300 patients dur- ing clinical trials [97, 98]. A phase III, double-blind, ran- as a pro-drug, as it delivers two lodenafil molecules in vivo; dimerization reduces the polarity of the molecule, thus al- domized, placebo-controlled, parallel-group, dose-escalation lowing better oral absorption [116]. Clinical trials on this study was conducted to assess the tolerability and pharma- promising drug are being conducted to evaluate its efficacy cokinetic properties of single and multiple oral doses of ava- and tolerability [117]. A recent clinical trial on the efficacy nafil in healthy Korean male volunteers [99]. No serious and safety of lodenafil carbonate (40 mg or 80 mg) showed adverse events were reported at doses of 50 to 200 mg per day for 7 days; the most commonly reported side effects with an acceptable efficacy profile of the drug, with a significant improvement of IIEF-EF [118]. Interestingly, side effects, avanafil were mild and included headaches, flushing, nausea, including rhinitis, headache, flushing, and dizziness, oc- fatigue, nasal congestion and muscle cramps [96, 99]. curred in 28.7% of individuals treated with placebo, 40.9% Moreover, although its selectivity against PDE6 is 120-fold of those treated with 40 mg lodenafil carbonate, and 49.5% higher than sildenafil (16-fold) and vardenafil (21-fold) [99], of those treated with 80 mg lodenafil carbonate. no color vision disturbances have been reported during clini- cal trials. Sildenafil Nitrate (NCX-911) Recently, a large phase III, double-blind, placebo- Sildenafil nitrate is a novel nitrated derivative of silde- controlled study showed that avanafil (both 100mg and nafil that act also as an NO donor [119-123]. 200mg) was effective and well tolerated in the treatment of This interesting dualistic mechanism might produce an ED following bilateral nerve-sparing radical prostatectomy [100]. increase of guanylyl cyclase activity, thus making the com- pound more effective than sildenafil citrate in treating ED, as Udenafil (DA-8159) yet demonstrated in animal models [120, 124]. Growing re- search is aimed at investigating the effects of the concomi- Udenafil is an oral PDEI currently marketed in South tant use of sildenafil and NO donors on blood pressure in Korea and Russia under the name Zydena (DA-8159, Zy- ® humans, taking into account the potential cardiovascular risk dena , Dong-A Pharma Tech. Co. Ltd). Its selectivity to PDE5 is similar to that of sildenafil [101, 102], with a good [125]. safety profile. In a recent clinical trial, udenafil was com- Soluble Guanylate-cyclase Activators pared to placebo to assess its tolerability and pharmacoki- Mechanisms involving the soluble guanylate cyclase netic profile in a population of healthy subjects [72]; no seri- (sGC) as a possible target for alternative treatments are under ous adverse events related to udenafil have been reported. investigation, since an increased activity of this enzyme Another study confirmed the efficacy and good safety profile of udenafil, with mild adverse events limited to facial flush- could result in higher concentrations of intracellular cGMP with a subsequent smooth muscles relaxation. ing, nasal stuffiness, ocular hyperemia and headache. Fi- nally, a recent meta-analysis of randomized controlled trials YC-1 and BAY 41-2272 are two exogenous sGC activa- comparing udenafil vs placebo on 1109 patients with ED tors that are currently considered the most promising thera- confirmed the efficacy and good tolerability of the drug peutic targets see Fig. (1) [126]. [103-106]. The drug was effective and safe for the treatment YC-1 of ED in hypertensive men taking concomitant antihyperten- sive agents [107]; furthermore, given together with an alpha- The benzylindazole derivative YC-1 (3-5-hydroxy- blocker to patients with lower urinary tract symptoms and methyl-2-furyl-1-benzyl-indazole) determines marked sGC ED, it improved both conditions and was well tolerated activation [127-129], and its systemic injection has been [108]. proven to improve penile erection in animal models [130]. Mirodenafil (SK3530) YC-1-induced sGC stimulation is NO-independent, given that its effect on erectile function occurred even after Mirodenafil is a pyrrolopyrimidinone compound mar- G administration of N -nitro-L-arginine methyl-ester (L- keted in South Korea for the treatment of ED. A phase III NAME), a NO synthase inhibitor [129-131]. It has also study demonstrated a mean 7.6 and 11.6 point improvement 46 Recent Patents on CNS Drug Discovery, 2014, Vol. 9, No. 1 Calabrò et al.

F

N N HO N O

N N NN

NH2

YC-1 BAY 41-2272

Fig. (1). Chemical structures of soluble guanylate-cyclase activators. been reported that YC-1 stimulates the synthesis and re- without producing the typical apomorphine adverse events lease of NO from local stores, acting as a non-specific [143, 144]. PDEi [132, 133]. Consequently, drugs having D4 receptors agonistic activ- BAY41-2272 ity have been developed to evaluate their potential erectogenic activity. To this end, a new class of The pyrazolopyridine derivative BAY41-2272 is another benzylindazole compounds has been recently discovered and NO-independent activator of the sGC. with a higher affinity optimized to produce highly selective D4 agonism [145]. and potency [134- 136]. An interesting study [134] has shown a BAY41-2272 ABT-724 concentration-dependent relaxation of human and rabbit cav- ernous strips, and a partial restoration of the nitrergic re- ABT-724 (2-(4-Pyridin-2-ylpiperazin-1-ylmethyl)-1H- sponse after NO-synthase inhibition with L-NAME. benzimidazole) is a potent and selective D4 receptor ago- nist, currently under investigation for its pro-erectile poten- Two other sGC stimulators, BAY 41-8543 and BAY tial, when injected into the cerebral ventricles [146]. The 60-2770, have been recently investigated for erectile re- effects of the combination of ABT-724 with sildenafil have sponse after intracavernosal injections in anesthetized rats, been also investigated in rats, revealing a 10-fold increase with similar results [137, 138]. A forth sGC stimulator, in erectile events [146]. These data imply that the combina- BAY 60-4552, when co-administered with vardenafil, dis- tion of a centrally acting with a peripherally acting agent closed a synergistic effect on relaxation of corpus caverno- might be beneficial for the treatment of individuals suffer- sum tissue of patients with ED non-responders to PDE5-I ing from ED. [139]. Potassium Channel Activators Azulene Derivatives Potassium channels seems to play a pivotal role in regu- Based on experimental evidences with the piperazin- lation of smooth muscle tone in several tissues, as they are ylmethyl substituted azulene FAUC 3019, a dopamine D4 able to regulate the resting membrane potential of the cell, receptor partial agonist that showed a strong pro-erectile attenuating the level of their excitation. Recent studies have effect in rats [147], a series of azulenylmethylpiperazines demonstrated the importance of the metabolically regulated was synthesized. Receptor binding experiments revealed K-ATP channel and the larger calcium sensitive maxi-K- that, among these, the N,N-dimethylaminomethyl substituted channel in eliciting human penile erection [140]. Novel azulene 11 was the most potent D4 partial agonist. When this compounds, including the K-channel activators pinacidil, candidate was investigated for its ability to stimulate penile cromakalim, lemakalim, and nicorandil, have been shown to erection in an in vivo animal model with male rats, it re- be effective in animal model, but their capacity in inducing vealed superior potency in low concentrations when com- erection in humans is still unknown [141]. pared to apomorphine [148].

CENTRALLY ACTING COMPOUNDS Melanocortin Receptor Agonists Dopaminergic Agonists The accidental finding that men involved in a derma- tologic clinical trial on the melanocortin receptor agonist Dopaminergic agonists may be a suitable alternative in melanotan-II (MT-II) reported unexpected erections lead to men with both cardiovascular disease and ED, whose condi- the development of melanocortin-based compounds for the tion may exclude treatment with PDE5Is [142]. Unfortu- treatment of ED [149]. nately most of them, including apomorphine, may cause side important side effects so to significantly limit their use for Since then, several studies showing that intravenously or this purpose [143]. subcutaneous administration of MT-II to men with organic and psychogenic ED enhances sexual arousal and penile Beyond D2 receptors, also D4 selective dopaminergic erections have been conducted [150-152]. agonists showed to be involved in penile erection, but Treatments of Neurogenic ED Recent Patents on CNS Drug Discovery, 2014, Vol. 9, No. 1 47

Despite the Growing Interest in Melanocortin Receptor- ferentiation and therapeutic potential, but easier and safer to Specific Peptides, to Date no Melanocortin Receptor-specific obtain, was developed [166]. Compound has been Approved for SD Treatment. Interestingly, BMSCs transduced with eNOs seems to be able to improve the erectile function in aged rats [167] Bremelanotide (PT-141) whereas embryonic SCs transfected with Brain-Derived Neu- Bremelanotide is an active metabolite of MT-II with a rotrophic Factor (BDNF) could restore erection of the rats good affinity for MCR-3 and MCR-4 [153], determining a whose cavernous nerves were experimentally damaged [168]. statistically significant erectile response [154-156]. A further study showed that injections with mesenchymal stem cells infected with recombinant adenoviruses expressing The efficacy of the drug (at a dose of 5 mg) has been con- human BDNF in rats with ED caused by cavernous nerve in- firmed in a 12 week placebo-controlled clinical trial involving jury, significantly preserved the erectile function [169]. non-diabetic men with ED [157], whereas safety and efficacy Moreover, intracavernous injection of p75 derived multipotent of coadministration of subtherapeutic doses of bremelanotide stromal cells in a rat model of bilateral cavernous nerve injury plus sildenafil was investigated in men with ED [158]. resulted in a significant improvement in erection [170].

Gene and Stem Cell Therapy PATENTS The gene therapy in ED may potentially act on the cause In smooth muscle cells, Rho proteins are responsible for of the disease by restoring defective functions and/or correct- the calcium sensitization during smooth muscle contrac- ing the expression of a mutant gene. In order to allow the tion. In particular, the RhoA and its specific kinase transfer of genetic material to the target cell, both viral and (ROCK) play a crucial role in maintaining the flaccid state non-viral methods have been used [159, 160]. Local gene of the penis. Furthermore, it has been observed that bilat- therapy in particular may be considered a convincing treat- eral cavernous nerve injury (BCNI) results in upregulation ment option for ED in diverse pathological conditions, with of ROCK signaling in the penis which is linked to ED in an regard to cavernous nerve injury [161]. Unfortunately, al- animal model of post-prostatectomy ED. Thus, numerous most all available data are limited to preclinical trials on patents have recently appeared claiming applications of animals, except for a phase I clinical trial in individuals with Rho-kinase inhibitors in the treatment of cardiovascular ED, [162] showing promising results after a single intracav- diseases, including coronary heart diseases, atherosclerosis, ernous injection of a plasmid vector that expresses the gene  restenosis, cerebral ischemia [171-173]. Some of them (Y- encoding the -subunit of the maxi-K channel. 27632, HA-1077, SAR-407899) have shown a potential to Stem cells (SCs) are endowed with the capacity to self- elicit an erectile response in rat models, including in BCNI- renew and to differentiate into various cell types, depending associated ED [174-177]. In addition, since inhibition of on the signals that they received [163]. Adult bone marrow ROCK may lead to smooth muscle relaxation with a SCs (BMSCs) are the best studied SCs and have the potential mechanism that is independent of NO or cGMP, the use of to treat a wide variety of diseases, including ED [164]. The these agents may offer a therapeutic benefit in those cases effect of KCNMA1 transfected bone marrow-mesenchymal where NO bioavailability is attenuated (and thus PDE5Is stem cells (BM-MSCs) on the improvement of erectile func- are less efficacious), such as in diabetic patients, where the tion was assessed in sixty male Sprague-Dawley rats with development of ED seems to be at least partially mediated diabetes mellitus-induced erectile dysfunction. Results directly by ROCK [94]. showed that KCNMA1 transfected MSCs, injected intracav- Quinolines and quinolones derivative applications have ernously, displayed a significant improvement of erectile been registered as patents for the treatment of sexual dys- function in diabetic rats, probably by enhancing the positive function in males and females, including but not limited to effect of MSCs [165]. More recently, an adipose tissue- ED see Fig. (2) [178-180]. derived SCs virtually identical to bone marrow ones in dif-

Br

N N N O N H N Quinoline Isoquinoline 2-oxoquinoline 5-bromoquinoline 1-methylisoquinoline

O O O O N N S S N N O N O O H F N F N

Flosequinan Sulfone of flosequinan Cilostazol

Fig. (2). Chemical structures of new phosphodiesterase type III inhibitors. 48 Recent Patents on CNS Drug Discovery, 2014, Vol. 9, No. 1 Calabrò et al.

These compounds, having different routes of administra- CONFLICT OF INTEREST tion, are expected to exhibit an erectogenic activity because The author(s) confirm that this article content has no con- of their selective inhibitor activity toward PDE3, providing flicts of interest. beneficial therapeutic effects through a mechanism of action not involving cGMP (as for traditional PDE5Is) with possi- ble advantages in terms of efficacy or tolerability. Among ACKNOWLEDGEMENTS these derivatives, flosequinan has already been shown to be Declared none. useful in the treatment of heart failure, with a good safety profile. In addition, since several quinolines derivatives may DISCLOSURE selectively open the ATP-sensitive potassium ion channels, thus hyperpolarizing the cell and decreasing cellular excit- The authors state that this is an updated version of our ability, these compounds have been proposed for the treat- previous manuscript "Current and future therapies of erectile ment of disorders related to potassium ion channels, includ- dysfunction in neurological disorders" [195]. ing ED [181]. Recently, two groups of novel potassium channel openers (benzopyran derivatives and tricyclic dihy- REFERENCES dropyrazine derivatives) have been registered for the same [1] Maas R, Schwedhelm E, Albsmeier J, Böger RH. The pathophysi- clinical applications [182, 183], whereas cilostazol, a PDE3 ology of erectile dysfunction related to endothelial dysfunction and inhibitor, also acts as a direct vasodilator [184] beyond sup- mediators of vascular function. Vasc Med 2002; 7: 213-25. pressing platelet aggregation. [2] Sáenz de Tejada I, Angulo J, Cellek S, González-Cadavid N, Hea- ton J, Pickard R, et al. Physiology of erectile function. J Sex Med A new class of centrally acting dopamine agonists [185], 2004; 1: 254-65. showing a high affinity for D2 and D3 receptors, have sug- [3] Gratzke C, Angulo J, Chitaley K, Dai Y, Kim NN, Paick J, et al. gested a possible beneficial effect on different sexual dys- Anatomy, Physiology, and pathophysiology of erectile dysfunction. functions such as ED. J Sex Med 2010; 7: 445-75. [4] Steers WD. Neural pathways and central sites involved in penile Several patents, including peptidomimetic compounds, erection: Neuroanatomy and clinical implications. Neurosci Biobe- have been assigned to a group of peptides with structural hav Rev 2000; 24: 507-16. similarities to melanocortin receptor molecular regions for [5] Sachs BD. Placing erection in context: the reflexogenic- future applications in the treatment of male and female sex- psychogenic dichotomy reconsidered. Neurosci Biobehav Rev 1995; 19: 211-24. ual dysfunction [186-191]. Some of these cyclic peptides [6] Giuliano F, Rampin O. Neural control of erection. Physiol Behav were tested in rat penile erection studies using bremelanotide 2004; 83: 189-201. as a positive control, showing to produce a statistically sig- [7] Lambert MV. Seizures, hormones and sexuality. Seizure 2001; 10: nificant increase in observed spontaneous erections com- 319-40. pared to vehicle controls [191]. [8] Smaldone M, Sukkarieh T, Reda A, Khan A. Epilepsy and erectile dysfunction: A review. Seizure 2004; 13: 453-9. Finally, supplementation with novel L-arginine deriva- [9] Zorzon M, Zivadinov R, Monti Bragadin L, Moretti R, De Masi R, tives or inhibition of arginase activity have been proposed Nasuelli D, et al. Sexual dysfunction in multiple sclerosis: A 2-year for local or systemic use, with the aim of increasing the level follow-up study. J Neurol Sci 2001; 187: 1-5. of nitric oxide [192], and thus serving for the treatment of a [10] Foley FW, La Rocca NG, Sanders AS, Zemon V. Rehabilitation of number of diseases and conditions, including but not limited intimacy and sexual dysfunction in couples with multiple sclerosis. Mult Scler 2001; 7: 417-22. to ED [193]. Recently, a novel compound - TP508 – has [11] Dimitriadis F, Karakitsios K, Tsounapi P, Tsambalas S, Loutradis shown to block the up-regulation of arginase associated with D, Kanakas N, et al. Erectile function and male reproduction in endothelial dysfunction and by promoting the activation or men with spinal cord injury: A review. Andrologia 2010; 42: 139- up-regulation of nitric oxide synthase, thereby increasing the 65. production of nitric oxide in a dose-dependent manner [194]. [12] Kimura M, Murata Y, Shimoda K, Robinson RG. Sexual dysfunc- tion following stroke. Compr Psychiatry 2001; 42: 217-22. [13] Pistoia F, Govoni S, Boselli C. Sex after stroke: A CNS only dys- CURRENT & FUTURE DEVELOPMENTS function? Pharmacol Res 2006; 54: 11-8.

PDE5Is are considered the treatment of choice for neuro- [14] Papatsoris AG, Deliveliotis C, Singer C, Papapetropoulos S. Erec- tile dysfunction in Parkinson's disease. Urology 2006; 6: 447-51. genic ED by both patients and health care professionals. In- [15] Alves M, Conceicao I, Luis ML. Neurophysiological evaluation of deed, many new PDE5Is are candidates to enter the market sexual dysfunction in familial amyloidotic polyneuropathy- in forthcoming years, since new classes of drugs for ED un- Portuguese type. Acta Neurol Scand 1997; 96: 163-66. dergoing clinical trials are at the moment far away from [16] Burk K, Weiss A. Impotence after recovery from Guillan Barre clinical practice, possibly with the exception of melanocortin Syndrome. N J Med 1998; 95: 31-4. agonists. Since the spinal and supraspinal control of erection [17] Lundberg P, Ertekin C, Ghezzi A, Swash M, Vodusek D. Neuro- sexology. Eur J Neurol 2001; 8 (supp 3): 2-24. involving several and different transmitters (including do- [18] Francis SH, Corbin JD. Sildenafil: efficacy, safety, tolerability and pamine, noradrenaline, serotonin, nitric oxide, oxytocin, and mechanism of action in treating erectile dysfunction. Expert Opin ACTH/MSH) is still only partly known, detailed knowl- Drug Metab Toxicol 2005; 1: 283-93. edge of these systems will be important in the discovery of [19] Keating GM, Scott LJ. Vardenafil: A review of its use in erectile novel pharmacological agents for ED treatment. Moreover, dysfunction. Drugs 2003; 63: 2673-703. studies of interactions between different transmit- [20] Coward RM, Carson CC. Tadalafil in the treatment of erectile dysfunction. Ther Clin Risk Manage 2008; 4: 1315-29. ters/modulators may be the basis for new and possibly more [21] Shindel AW. 2009 update on phosphodiesterase type 5 inhibitor effective combination therapies. therapy part 2: Updates on optimal utilization for sexual concerns and rare toxicities in this class. J Sex Med 2009; 6: 2352-64. Treatments of Neurogenic ED Recent Patents on CNS Drug Discovery, 2014, Vol. 9, No. 1 49

[22] Hatzimouratidis K, Hatzichristou DG. Looking to the future for [46] O'Sullivan JD, Hughes AJ. Apomorphine induced penile erections erectile dysfunction therapies. Drugs 2008; 68: 231-50. in Parkinson's disease, Mov Disord 1998; 13: 536-39. [23] Eardley I, Donatucci C, Corbin J, El-Meliegy A, Hatzimouratidis [47] van Ahlen H, Piechota HJ, Kias HJ, Brennemann W, Klingmüller K, McVary K, et al. Pharmacotherapy for erectile dysfunction. J D. Opiate antagonists in erectile dysfunction: A possible new Sex Med 2010; 7: 524-40. treatment option? Results of a pilot study with naltrexone. Eur Urol [24] Andersson KE. Pharmacology of penile erection. Pharmacol Rev 1995; 28: 246-50. 2001; 53: 417-50. [48] Sathe RS, Komisaruk BR, Ladas AK, Godbole SV. Naltrexone- [25] Kandeel FR, Koussa VK, Swerdloff RS. Male sexual function and induced augmentation of sexual response in men. Arch Med Res its disorders: Physiology, pathophysiology, clinical investigation, 2001; 32: 221-6. and treatment. Endocr Rev 2001; 22: 342-88. [49] Enzlin P, Vanderschueren D, Bonte L, Vanderborght W, Declercq [26] Feifer A, Carrier S. Pharmacotherapy for erectile dysfunction. G, Demyttenaere k. Trazodone a double blind, placebo-controlled, Expert Opin Investig Drugs 2008; 17: 679-90. randomized study of its effects in patients with erectile dysfunction [27] Lombardi G, Macchiarella A, Del Popolo G. Efficacy and safety of without major organic findings. Int J Impot Res 2000; 12: 223-8. tadalafil for erectile dysfunction in patients with multiple sclerosis. [50] Stryjer R, Spivak B, Strous RD, Shiloh R, Harary E, Polak L, et al. J Sex Med 2010; 7: 2192-200. Trazodone for the treatment of sexual dysfunction induced by sero- [28] Xiao Y, Wang J, Luo H. Sildenafil citrate for erectile dysfunction tonin reuptake inhibitors: A preliminary open-label study. Clin in patients with multiple sclerosis. Cochrane Database Syst Rev Neuropharmacol 2009; 32: 82-4. 2012; 4: CD009427. [51] Taneja R. A rational combination pharmacotherapy in men with [29] Lombardi G, Macchiarella A, Cecconi F, Del Popolo G. Ten-year erectile dysfunction who initially failed to oral sildenafil citrate follow-up of sildenafil use in spinal cord-injured patients with erec- alone: A pilot study. J Sex Med 2007; 4: 1136-41. tile dysfunction. J Sex Med 2009; 6: 3449-57. [52] Tamler R, Mechanick JI. Dietary supplements and nutraceuticals in [30] Soler JM, Previnaire JG, Denys P, Chartier-Kastler E. Phosphodi- the management of andrologic disorders. Endocrinol Metab Clin esterase inhibitors in the treatment of erectile dysfunction in spinal North Am 2007; 36: 533-52. cord-injured men. Spinal Cord 2007; 45: 169-73. [53] Chen J, Wollman Y, Chernichovsky T, Iaina A, Sofer M, Matzkin [31] Matos G, Scorza FA, Cavalheiro EA, Tufik S, Andersen ML. H. Effect of oral administration of high dose nitric oxide donor L- PDEI-5 for erectile dysfunction: A potential role in seizure suscep- arginine in men with organic erectile dysfunction: Results of a tibility. J Sex Med 2012; 9: 2111-21. double-blind, randomized, placebo-controlled study. BJU Int 1999; [32] Giammusso B, Raffaele R, Vecchio I, Giammona G, Ruggieri M, 83: 269-73. Nicoletti G, et al. Sildenafil in the treatment of erectile dysfunction [54] Neuzillet Y, Hupertan V, Cour F, Botto H, Lebret T. A random- in elderly depressed patients with idiopathic Parkinson’s disease. ized, double-blind, crossover, placebo-controlled comparative Arch Gerontol Geriatr 2002; Suppl 8: 157-63. clinical trial of arginine aspartate plus adenosine monophosphate [33] Hussain IF, Brady CM, Swinn MJ, Mathias CJ, Fowler CJ. Treat- for the intermittent treatment of male erectile dysfunction. Androl- ment of erectile dysfunction with sildenafil citrate (Viagra) in park- ogy 2013; 1: 223-8. insonism due to Parkinson’s disease or multiple system atrophy [55] Cohen, A. Method for treating sexual dysfunction disorders with with observations on orthostatic hypotension. J Neurol Neurosurg compositions containing Ginkgo Biloba. US5897864A (1999). Psychiatry 2001; 71: 371-4. [56] Choi YD, Park CW, Jang J, Kim SH, Jeon HY, Kim WG, et al. [34] Gilad R, Lampl Y, Eshel Y, Sadeh M. Tonic-clonic seizures in Effects of Korean ginseng berry extract on sexual function in men patients taking sildenafil. BMJ 2002; 325: 869. with erectile dysfunction: A multicenter, placebo-controlled, dou- [35] Magheli A, Burnett AL. Erectile dysfunction following prostatec- ble-blind clinical study. Int J Impot Res 2013; 25: 45-50. tomy: Prevention and treatment. Nat Rev Urol 2009; 6: 415-27. [57] Cavallini G, Caracciolo S, Vitali G, Modenini F, Biagiotti G. Car- [36] Basal S, Wambi C, Acikel C, Gupta M, Badani K. Optimal strategy nitine versus androgen administration in the treatment of sexual for penile rehabilitation after robot-assisted radical prostatectomy dysfunction, depressed mood, and fatigue associated with male ag- based on preoperative erectile function. BJU Int 2013; 111: 658-65. ing. Urology 2004; 63: 641-6. [37] Porst H, Hell-Momeni K, Büttner H. Chronic PDE-5 inhibition in [58] Cipolla MJ, Nicoloff A, Rebello T, Amato A, Porter JM. patients with erectile dysfunction - a treatment approach using ta- Propionyl-L-carnitine dilates human subcutaneous arteries through dalafil once-daily. Expert Opin Pharmacother 2012; 13: 1481-94. an endothelium-dependent mechanism. J Vasc Surg 1999; 29: [38] Shindel AW. 2009 update on phosphodiesterase type 5 inhibitor 1097-103. therapy part 1: Recent studies on routine dosing for penile rehabili- [59] Gianfrilli D, Lauretta R, Di Dato C, Graziadio C, Pozza C, De tation, lower urinary tract symptoms, and other indications (CME). Larichaudy J, et al. Propionyl-L-carnitine, L-arginine and niacin in J Sex Med 2009; 6: 1794-808. sexual medicine: a nutraceutical approach to erectile dysfunction. [39] Traish A, Gupta S, Gallant C, Huang YH, Goldstein I. Phentola- Andrologia 2012; 44 Suppl 1: 600-4. mine mesylate relaxes penile corpus cavernosum tissue by adrener- [60] Giovannoni MP, Vergelli C, Graziano A, Dal Piaz V. PDE5 inhibi- gic and nonadrenergic mechanisms. Int J Impot Res 1998; 10: 215- tors and their applications. Curr Med Chem 2010; 17: 2564-87. 23. [61] Coombs PG, Heck M, Guhring P, Narus J, Mulhall JP. A review of [40] Goldstein I. Oral phentolamine: an alpha-1, alpha-2 adrenergic outcomes of an intracavernosal injection therapy programme. BJU antagonist for the treatment of erectile dysfunction. Int J Impot Res Int 2012; 110: 1787-91. 2000; 12 Suppl 1: S75-80. [62] Poch G, Kukovetz WR. Papaverine-induced inhibition of phos- [41] Saad MA, Eid NI, Abd El-Latif HA, Sayed HM. Potential effects phodiesterase activity in various mammalian tissues. Life Sci 1971; of yohimbine and sildenafil on erectile dysfunction in rats. Eur J 10: 133-44. Pharmacol 2013; 700: 127-33. [63] Fallon B. Intracavernous injection therapy for male erectile dys- [42] Morales A. Yohimbine in erectile dysfunction: The facts. Int J function. Urol Clin North Am 1995; 22: 833-45. Impot Res 2000; 12 (suppl 1): S70-S74. [64] Costa P, Potempa AJ. Intraurethral alprostadil for erectile dysfunc- [43] Paick JS, Lee SW. The neural mechanism of apomorphine-induced tion: A review of the literature. Drugs 2012; 72: 2243-54. erection: An experimental study by comparison with electrostimu- [65] Linet OI, Ogrinc FG. Efficacy and safety of intracavernosal alpros- lation-induced erection in rat model. J Urol 1994; 152: 2125-8. tadil in men with erectile dysfunction. The Alprostadil Study [44] Von Keitz AT, Stroberg P, Bukofzer S, Mallard N, Hibberd M. A Group. N Engl J Med 1996; 334: 873-7. European multicentre study to evaluate the tolerability of apomor- [66] McCullough AR, Hellstrom WG, Wang R, Lepor H, Wagner KR, phine sublingual administered in a forced dose-escalation regimen Engel JD. Recovery of erectile function after nerve sparing radical in patients with erectile dysfunction. BJU Int 2002; 89: 409-15. prostatectomy and penile rehabilitation with nightly intraurethral [45] Chaudhuri KR, Schapira AH. Non-motor symptoms of Parkinson's alprostadil versus sildenafil citrate. J Urol 2010; 183: 2451-6. disease: Dopaminergic pathophysiology and treatment. Lancet Neurol 2009; 8: 464-74. 50 Recent Patents on CNS Drug Discovery, 2014, Vol. 9, No. 1 Calabrò et al.

[67] Dinsmore WW, Wyllie MG. Vasoactive intestinal polypep- [89] Kendirci M, Walls MM, Hellstrom WJ. Central nervous system tide/phentolamine for intracavernosal injection in erectile dysfunc- agents in the treatment of erectile dysfunction. Urol Clin North Am tion. BJU Int 2008; 102: 933-7. 2005; 32: 487-501. [68] Seyam R, Mohamed K, Akhras AA, Rashwan H. A prospective [90] Eros D, Szántai-Kis C, Kiss R, Kéri G, Hegymegi-Barakonyi B, randomized study to optimize the dosage of trimix ingredients and Kövesdi I, et al. Structure -activity relationships of PDE5 inhibi- compare its efficacy and safety with prostaglandin E1. Int J Impot tors. Curr Med Chem 2008; 15: 1570-85. Res 2005; 17: 346. [91] Cote RH. Characteristics of Photoreceptor PDE (PDE6): Similari- [69] Deforge D, Blackmer J, Garritty C, Yazdi F, Cronin V, Barrowman ties and differences to PDE5. Int J Impot Res 2004; 16 Suppl 1: N, et al. Male erectile dysfunction following spinal cord injury: a S28-33. systematic review. Spinal Cord 2006; 44: 465-73. [92] Sweetnam P, Campbell S, Georgan M, Kirk B, McGonigle S, Para- [70] Chancellor MB, Rivas DA, Panzer DE, Freedman MK, Staas WE dise E, et al. SLx-2101, a novel long-lasting phosphodiesterase-5 Jr. Prospective comparison of topical minoxidil to vacuum con- (PDE5) inhibitor for erectile dysfunction: In vivo and in vitro stud- striction device and intracorporeal papaverine injection in treatment ies. J Sex Med 2006; 3 Suppl 1: 29 -30. of erectile dysfunction due to spinal cord injury. Urology 1994; 43: [93] Prince WT, Campbell AS, Tong W, Sweetnam P, Rose R, Gold- 365-9. stein I, et al. SLx-2101, a new long-acting PDE5 inhibitor: Pre- [71] Hellstrom WJ, Bennett AH, Gesundheit N, Kaiser FE, Lue TF, liminary safety, tolerability, PK and endothelial function effects in Padma-Nathan H, et al. A double-blind, placebo-controlled evalua- healthy subjects. J Sex Med 2006; 3 Suppl 1: 29-30. tion of the erectile response to transurethral alprostadil. Urology [94] Albersen M, Shindel AW, Mwamukonda KB, Lue TF. The future 1996; 48: 851-6. is today: Emerging drugs for the treatment of erectile dysfunction. [72] Werthman P, Rajfer J. MUSE therapy: Preliminary clinical obser- Expert Opin Emerg Drugs 2010; 15: 467-80. vations. Urology 1997; 50: 809-11. [95] Omori K, Fujishige K. Avanafil has the potential for the treatment [73] Bodner DR, Seftel A, Krueger B. Intraurethral alprostadil (MUSE) of erectile dysfunction with selective phosphodiesterase-5. J Sex for treatment of erectile dysfunction in spinal cord injured patients. Med 2006; 3 Suppl 3: 221-2. J Spinal Cord Med 1998; 21:186-7. [96] Peterson C, Swearingen D. Pharmacokinetics of avanafil, a new [74] Witherington R. Vacuum constriction device for management of PDE5 inhibitor being developed for erectile dysfunction. J Sex erectile impotence. J Urol 1989; 141: 320-2. Med 2006; 3 Suppl 3: 253-4. [75] Baltaci S, Aydos K, Kosar A, Anafarta K. Treating erectile dys- [97] Wang R, Burnett AL, Heller WH, Omori K, Kotera J, Kikkawa K, function with a vacuum tumescence device: A retrospective analy- et al. Selectivity of Avanafil, a PDE5 inhibitor for the treatment of sis of acceptance and satisfaction. Br J Urol 1995; 76: 757-60. erectile dysfunction: Implications for clinical safety and improved [76] De Palma RG, Olding M, Yu GW, Schwab FJ, Druy EM, Miller tolerability. J Sex Med 2012; 9: 2122-9. HC, et al. Vascular interventions for impotence: Lessons learned. J [98] Goldstein I, Jones LA, Belkoff LH, Karlin GS, Bowden CH, Peter- Vasc Surg 1995; 21: 576-84. son CA, et al. Avanafil for the treatment of erectile dysfunction: A [77] Manning M, Junemann KP, Scheepe JR, Braunn P, Krautschick A, multicenter, randomized, double-blind study in men with diabetes Alken P. Long-term follow up and selection criteria for penile re- mellitus. Mayo Clin Proc 2012; 87: 843-52. vascularization in erectile failure. J Urol 1998; 160: 1680-4. [99] Mulhall JP, Burnett AL, Wang R, McVary KT, Moul JW, Bowden [78] Dicks B, Bastuba M, Goldstein I. Penile revascularization- CH, et al. A phase 3, placebo controlled study of the safety and ef- contemporary update. Asian J Androl 2013; 15: 5-9. ficacy of avanafil for the treatment of erectile dysfunction after [79] Freedman AL, Costa Neto F, Mehringer CM, Rajfer J. Long-term nerve sparing radical prostatectomy. J Urol 2013; 189: 2229-36. results of penile vein ligation for impotence from venous leakage. J [100] Jung J, Choi S, Cho SH, Ghim JL, Hwang A, Kim U, et al. Toler- Urol 1993; 149: 1301-3. ability and pharmacokinetics of avanafil, a phosphodiesterase type [80] Lewis RW. Long-term results of penile prosthetic implants. Urol 5 inhibitor: a single- and multiple-dose, double-blind, randomized, Clin North Am 1995; 22: 847-56. placebo-controlled, dose-escalation study in healthy Korean male [81] Chung E, Van CT, Wilson I, Cartmill RA. Penile prosthesis im- volunteers. Clin Ther 2010; 32: 1178-87. plantation for the treatment for male erectile dysfunction: clinical [101] Doh H, Shin CY, Son M, Ko JI, Yoo M, Kim SH, et al. Mechanism outcomes and lessons learnt after 955 procedures. World J Urol of erectogenic effect of the selective phosphodieterease type 5 in- 2013; 31: 591-5. hibitor, DA-8159. Arch Pharm Res 2002; 25: 873-8. [82] Trost LW, McCaslin R, Linder B, Hellstrom WJ. Long-term out- [102] Ortaç M, Çayan S, Çalikan MK, Yaman MÖ, Okutucu TM, comes of penile prostheses for the treatment of erectile dysfunction. Semerci MB, et al. Efficacy and tolerability of udenafil in Turkish Expert Rev Med Devices 2013; 10: 353-66. men with erectile dysfunction of psychogenic and organic aetiol- [83] Kim YD, Yang SO, Lee JK, Jung TY, Shim HB. Usefulness of a ogy: A randomized, double-blind, placebo-controlled study. Androl malleable penile prosthesis in patients with a spinal cord injury. Int 2013; 1: 549-55. J Urol 2008; 15: 919-23. [103] Ding H, Du W, Wang H, Zhang L, Wang Z, Du C, et al. Efficacy [84] Megas G, Papadopoulos G, Stathouros G, Moschonas D, Gkialas I, and safety of udenafil for erectile dysfunction: A meta-analysis of Ntoumas K. Comparison of efficacy and satisfaction profile, be- randomized controlled trials. Urology 2012; 80:134-9. tween penile prosthesis implantation and oral PDE5 inhibitor Tada- [104] Kim BH, Lim HS, Chung JY, Kim JR, Lim KS, Sohn DR, et al. lafil therapy, in men with nerve-sparing radical prostatectomy erec- Safety, tolerability and pharmacokinetics of udenafil, a novel PDE- tile dysfunction. BJU Int 2013; 112: E169-76. 5 inhibitor, in healthy young korean subjects. Br J Clin Pharmacol [85] Gilbert DA, Williams MW, Horton CE, Terzis JK, Winslow BH, 2008; 65: 848-54. Gilbert DM, et al. Phallic reinnervation via the pudendal nerve. J [105] Kim TE, Kim BH, Kim JR, Lim KS, Hong JH, Kim KP, et al. Urol 1988; 140: 295-9. Effect of food on the pharmacokinetics of the oral phosphodi- [86] Son H, Park K, Kim SW, Paick JS. Reasons for discontinuation of esterase 5 inhibitor udenafil for the treatment of erectile dysfunc- sildenafil citrate after successful restoration of erectile function. tion. Br J Clin Pharmacol 2009; 68: 43-6. Asian J Androl 2004; 6: 117-20. [106] Shin KH, Chung YJ, Kim BH, Kim TE, Kim HS, Cho JY, et al. [87] Hatzimouratidis K, Hatzichristou DG. A comparative review of the Effect of ketoconazole on the pharmacokinetics of udenafil in options for treatment of erectile dysfunction: Which treatment for healthy Korean subjects. Br J Clin Pharmacol 2010; 69: 307-10. which patient? Drugs 2005; 65: 1621-50. [107] Paick JS, Kim SW, Park YK, Hyun JS, Park NC, Lee SW, et al. [88] Gur S, Sikka SC, Hellstrom WJ. Novel phosphodiesterase-5 The efficacy and safety of udenafil [Zydena] for the treatment of (PDE5) inhibitors in the alleviation of erectile dysfunction due to erectile dysfunction in hypertensive men taking concomitant anti- diabetes and ageing-induced oxidative stress. Expert Opin Investig hypertensive agents. J Sex Med 2009; 6: 3166-76. Drugs 2008; 17: 855-64. [108] Chung BH, Lee JY, Lee SH, Yoo SJ, Lee SW, Oh CY. Safety and efficacy of the simultaneous administration of udenafil and an al- Treatments of Neurogenic ED Recent Patents on CNS Drug Discovery, 2014, Vol. 9, No. 1 51

pha-blocker in men with erectile dysfunction concomitant with [125] Webb DJ, Muirhead GJ, Wulff M. Sildenafil citrate potentiates the BPH/LUTS. Int J Impot Res 2009; 21: 122-8. hypotensive effects of nitric oxide donor drugs in male patients [109] Paick JS, Ahn TY, Choi HK, Chung WS, Kim JJ, Kim SC, et al. with stable angina. J Am Coll Cardiol 2000; 36: 25-31. Efficacy and safety of mirodenafil, a new oral phosphodiesterase [126] Evgenov OV, Pacher P, Schmidt PM, Hasko G, Schmidt HH, type 5 inhibitor, for treatment of erectile dysfunction. J Sex Med Stasch JP. NO-independent stimulators and activators of soluble 2008; 5: 2672-80. guanylate cyclase: Discovery and therapeutic potential. Nat Rev [110] Chung JH, Kang DH, Oh CY, Chung JM, Lee KS, Kim TH, et al. Drug Discov 2006; 5: 755-68. Safety and efficacy of once daily administration of 50 mg mirode- [127] Friebe A, Koesling D. Mechanism of YC-1-induced activation of nafil in patients with erectile dysfunction: A multicenter, double- soluble guanylyl cyclase. Mol Pharmacol 1998; 53: 123. blind, placebo controlled trial. J Urol 2013; 189: 1006-13. [128] Lee YC, Martin E, Murad F. Human recombinant soluble guanylyl [111] Shin HI, Lee J, Kim DK. Synthesis of 5-ethyl-2-{5-[4-(2- cyclase: Expression, purification and regulation. Proc Natl Acad hydroxyethyl)piperazin-1-ylsulfonyl]-2-n-propoxyphenyl}-7-n- Sci USA 2000; 97: 10763. propyl-3,5-dihydro-4H-pyrrolo[3,2-d]-[2-14C] pyrimidin-4- [129] Hsieh GC, O’Neill AB, Moreland RB, Sullivan JP, Brioni JD. YC- one•HCl(14C-SK3530•2HCl). J Label Compd Radiopharm 2006; 1 potentiates the nitric oxide/cyclic GMP pathway in corpus caver- 49: 1141-9. nosum and facilitates penile erection in rats. Eur J Pharmacol 2003; [112] Jung JY, Kim SK, Kim BS, Lee SH, Park YS, Kim SJ, et al. The 458: 183-9. penile erection efficacy of a new phosphodiesterase type 5 inhibi- [130] Mizusawa H, Hedlund P, Brioni JD, Sullivan JP, Andersson KE. tor, mirodenafil (SK3530), in rabbits with acute spinal cord injury. Nitric oxide independent activation of guanylate cyclase by YC-1 J Vet Med Sci 2008; 70: 1199-204. causes erectile responses in the rat. J Urol 2002; 167: 2276-81. [113] Kim BH, Yi S, Kim J, Lim KS, Kim KP, Lee B, et al. Influence of [131] Nakane M, Hsieh G, Miller LN, Chang R, Terranova MA, More- alcohol on the hemodynamic effects and pharmacokinetic proper- land RB, et al. Activation of soluble guanylate cyclase causes re- ties of mirodenafil: a single-dose, randomized-sequence, open- laxation of corpus cavernosum tissue: Synergism of nitric oxide label, crossover study in healthy male volunteers in korea. Clin and YC-1. Int J Impot Res 2002; 14: 121. Ther 2009; 31: 1234-43. [132] Wohlfart P, Malinski T, Ruetten H, Schindler U, Linz W, Schoe- [114] Choi YH, Lee YS, Lee MG, Kim TK, Lee BY. Pharmacokinetics nafinger K, et al. Release of nitric oxide from endothelial cells of mirodenafil, a new erectogenic, and its metabolite, SK3541, in stimulated by YC-1, an activator of soluble guanylyl cyclase. Br J rats: involvement of CYP1A1/2, 2B1/2, 2D subfamily, and 3A1/2 Pharmacol 1999; 128: 1316. for the metabolism of both mirodenafil and SK3541. J Pharm [133] Galle J, Zabel U, Hübner U, Hatzelmann A, Wagner B, Wanner C, Pharm Sci 2010; 13: 93-106. et al. Effects of the soluble guanylyl cyclase activator, YC-1, on [115] Lee HS, Park EJ, Ji HY, Kim SY, Im GJ, Lee SM, et al. Identifica- vascular tone, cyclic GMP levels and phosphodiesterase activity. tion of cytochrome P450 enzymes responsible for N-dealkylation Br J Pharmacol 1999; 127: 195-203. of a new oral erectogenic, mirodenafil. Xenobiotica 2008; 38: 21- [134] Kalsi JS, Rees RW, Hobbs AJ, Royle M, Kell PD, Ralph DJ, et al. 33. BAY41-2272, a novel nitric oxide independent soluble guanylate [116] Toque HA, Teixeira CE, Lorenzetti R, Okuyama CE, Antunes E, cyclase activator, relaxes human and rabbit corpus cavernosum in De Nucci G. Pharmacological characterization of a novel phos- vitro. J Urol 2003; 169: 761-6. phodiesterase type 5 (PDE5) inhibitor lodenafil carbonate on hu- [135] Stasch JP, Becker EM, Alonso-Alija C, Apeler H, Dembowsky K, man and rabbit corpus cavernosum. Eur J Pharmacol 2008; 591: Feurer A, et al. NO-independent regulatory site on soluble guany- 189-95. late cyclase. Nature 2001; 410: 212. [117] Mendes GD, dos Santos Filho HO, dos Santos Pereira A, Mendes [136] Bischoff E, Schramm A, Straub A, Feurer A, Stasch JP. BAY 41- FD, Ilha JO, Alkharfy KM, et al. A Phase I clinical trial of lode- 2272: A stimulator of soluble guanylate cyclase induces nitric ox- nafil carbonate, a new phosphodiesterase Type 5 (PDE5) inhibitor, ide-dependent penile erection in vivo. Urology 2003; 61: 464-7. in healthy male volunteers. Int J Clin Pharmacol Ther 2012; 50: [137] Lasker GF, Pankey EA, Allain AV, Dhaliwal JS, Stasch JP, Murthy 896-906. SN, et al. Analysis of erectile responses to BAY 41-8543 and mus- [118] Glina S, Fonseca GN, Bertero EB, Damião R, Rocha LC, Jardim carinic receptor stimulation in the Rat. J Sex Med 2013; 10: 704- CR, et al. Efficacy and tolerability of lodenafil carbonate for oral 18. therapy of erectile dysfunction: A phase III clinical trial. J Sex Med [138] Lasker GF, Pankey EA, Frink TJ, Zeitzer JR, Walter KA, Kadowitz 2010; 7: 1928-36. PJ. The sGC activator BAY 60-2770 has potent erectile activity in [119] Seidler M, Uckert S, Waldkirch E, Stief CG, Oelke M, Tsikas D, et the rat. Am J Physiol Heart Circ Physiol 2013; 304: H1670-9. al. In vitro effects of a novel class of nitric oxide (NO) donating [139] Albersen M, Linsen L, Tinel H, Sandner P, Van Renterghem K. compounds on isolated human erectile tissue. Eur Urol 2002; 42: Synergistic effects of BAY 60-4552 and vardenafil on relaxation of 523-8. corpus cavernosum tissue of patients with erectile dysfunction and [120] Muzaffar S, Shukla N, Srivastava A, Angelini GD, Jeremy JY. clinical phosphodiesterase type 5 inhibitor failure. J Sex Med 2013; Sildenafil citrate and sildenafil nitrate (NCX 911) are potent inhibi- 10: 1268-77. tors of superoxide formation and gp91phox expression in porcine [140] Spektor M, Rodriguez R, Rosenbaum RS, Wang HZ, Melman A, pulmonary artery endothelial cells. Br J Pharmacol 2005; 146: 109- Christ GJ. Potassium channels and human corporeal smooth mus- 17. cle cell tone: further evidence of the physiological relevance of the [121] Jeremy JY, Ballard SA, Naylor AM, Miller MA, Angelini GD. Maxi-K channel subtype to the regulation of human corporeal Effects of sildenafil, a type-5 cGMP phosphodiesterase inhibitor, smooth muscle tone in vitro. J Urol 2002; 167: 2628-35. and papaverine on cyclic GMP and cyclic AMP levels in the rabbit [141] Christ GJ. K channels as molecular targets for the treatment of corpus cavernosum in vitro. Br J Urol Int 1997; 79: 958-63. erectile dysfunction. J Androl 2002; 23: S10-9. [122] Jeremy JY, Angelini GD, Khan M, Mikhailidis DP, Morgan RJ, [142] Fagan TC, Buttler S, Marbury T, Taylor A, Edmonds A; SL APO Thompson CS, et al. Platelets, oxidant stress and erectile dysfunc- Study Group. Apomorphine Study Group. Cardiovascular safety of tion: an hypothesis. Cardiovasc Res 2000; 46: 50-4. sublingual apomorphine in patients on stable doses of oral anti- [123] Kalsi JS, Kell PD, Cellek S, Ralph DJ. NCX-911, a novel nitric hypertensive agents and nitrates. Am J Cardiol 2001; 88: 760-6. oxide-releasing PDE5 inhibitor relaxes rabbit corpus cavernosum [143] Mulhall J. Sublingual apomorphine for the treatment of erectile in the absence of endogenous nitric oxide. Int J Impot Res 2004; dysfunction. Expert Opin Investig Drug 2002; 11: 295-302. 16: 195-200. [144] Sanna F, Succu S, Hübner H, Gmeiner P, Argiolas A, Melis MR. [124] Shukla N, Jones R, Persad R, Angelini GD, Jeremy JY. Effect of Dopamine D2-like receptor agonists induce penile erection in male sildenafil citrate and a nitric oxide donating sildenafil derivative, rats: differential role of D2, D3 and D4 receptors in the paraven- NCX 911, on cavernosal relaxation and superoxide formation in tricular nucleus of the hypothalamus. Behav Brain Res 2011; 225: hypercholesterolaemic rabbits. Eur J Pharmacol 2005; 517: 224-31. 169-76. 52 Recent Patents on CNS Drug Discovery, 2014, Vol. 9, No. 1 Calabrò et al.

[145] Cowart M, Latshaw SP, Bhatia P, Daanen JF, Rohde J, Nelson SL, [165] He Y, He W, Qin G, Luo J, Xiao M. Transplantation KCNMA1 et al. Discovery of 2-(4-Pyridin-2-ylpiperazin-1-ylmethyl)-1H- modified bone marrow-mesenchymal stem cell therapy for diabetes benzimidazole (ABT-724), a dopaminergic agent with a novel mellitus-induced erectile dysfunction. Andrologia 2013 May 6. doi: mode of action for the potential treatment of erectile dysfunction. J 10.1111/and.12104. Med Chem 2004; 47: 3853-64. [166] Lin CS, Xin ZC, Deng CH, Ning H, Lin G, Lue TF. Recent ad- [146] Brioni JD, Moreland RB, Cowart M, Hsieh GC, Stewart AO, Hed- vances in andrology-related stem cell research. Asian J Androl lund P, et al. Activation of dopamine D4 receptors by ABT-724 in- 2008; 10: 171-5. duces penile erection in rats. Proc Natl Acad Sci USA 2004; 101: [167] Deng W, Bivalacqua TJ, Chattergoon NN, Hyman AL, Jeter JR Jr, 6758 -63. Kadowitz PJ. Adenoviral gene transfer of eNOS: high-level expres- [147] Löber S, Tschammer N, Huebner H, Melis MR, Argiolas A, Gme- sion in ex vivo expanded marrow stromal cells. Am J Physiol Cell iner P. The azulene framework as a novel arene bioisostere: Design Physiol 2003; 285: C1322-9. of potent dopamine D4 receptor ligands inducing penile erection. [168] Bochinski D, Lin GT, Nunes L, Carrion R, Rahman N, Lin CS, et ChemMedChem 2009; 4: 325-8. al. The effect of neural embryonic stem cell therapy in a rat model [148] Löber S, Hübner H, Buschauer A, Sanna F, Argiolas A, Melis MR, of cavernosal nerve injury. BJU Int 2004; 94: 904-9. et al. Novel azulene derivatives for the treatment of erectile dys- [169] Kim SJ, Choi SW, Hur KJ, Park SH, Sung YC, Ha YS, et al. Syn- function. Bioorg Med Chem Lett 2012; 22: 7151-4. ergistic effect of mesenchymal stem cells infected with recombi- [149] Hadley ME, Dorr RT. Melanocortin peptide therapeutics: Histori- nant adenovirus expressing human BDNF on erectile function in a cal milestones, clinical studies and commercialization. Peptide rat model of cavernous nerve injury. Korean J Urol 2012; 53: 726- 2006; 27: 921-30. 32. [150] Shadiack A, Sharma SD, Earle DC, Spana C, Hallam TJ. Melano- [170] Kendirci M, Trost L, Bakondi B, Whitney MJ, Hellstrom WJ, cortins in the treatment of male and female sexual dysfunction. Spees JL. Transplantation of nonhematopoietic adult bone marrow Curr Top Med Chem 2007; 7: 1137-44. stem/progenitor cells isolated by p75 nerve growth factor receptor [151] Wessells H, Fuciarelli K, Hansen J, Hadley ME, Hruby VJ, Dorr R, into the penis rescues erectile function in a rat model of cavernous et al. Synthetic melanotropic peptide initiates erections in men with nerve injury. J Urol 2010; 184: 1560-6. psychogenic erectile dysfunction: Double-blind, placebo controlled [171] Nagarathnam, D., Asgari, D., Shao, J., Liu, X., Khire, U., Wang, crossover study. J Urol 1998; 160: 389-93. C., Hart, B., Boyer, S., Weber, O., Lynch, M. Rho-Kinase Inhibi- [152] Martin WJ, MacIntyre DE. Melanocortin receptors and erectile tors. US20100137324A1 (2010). function. Eur Urol 2004; 45: 706-13. [172] Nagarathnam, D., Wang, C. Rho-Kinase Inhibitors. [153] King SH, Mayorov AV, Balse-Srinivasan P, Hruby VJ, Vanderah US20100249159A1 (2010). TW, Wessells H. Melanocortin receptors, melanotropic peptides [173] Nagarathnam, D., Khire, U., Asgari, D., Shao, J., Liu, X., Wang, and penile erection. Curr Top Med Chem 2007; 7: 1098-106. C., Hart, B., Weber, O., Lynch, M., Zhang, L., Wang, L. Rho- [154] Rosen RC, Diamond LE, Earle DC, Shadiack AM, Molinoff PB. Kinase Inhibitors. US20100216789A1 (2010). Valuation of the safety, pharmacokinetics and pharmacodynamic [174] Hannan JL, Albersen M, Kutlu O, Gratzke C, Stief CG, Burnett effects of subcutaneously administered PT-141, a melanocortin re- AL, et al. Inhibition of Rho-kinase Improves Erectile Function, In- ceptor agonist, in healthy male subjects and in patients with an in- creases Nitric Oxide Signaling and Decreases Penile Apoptosis in a adequate response to Viagra. Int J Impot Res 2004; 16: 135-42. Rat Model of Cavernous Nerve Injury. J Urol 2013; 189: 1155-61. [155] Diamond LE, Earle DC, Rosen RC, Willett MS, Molinoff PB. [175] Jiang X, Chitaley K. The promise of inhibition of smooth muscle Double blind, placebo-controlled evaluation of the safety, pharma- tone as a treatment for erectile dysfunction: Where are we now? Int cokinetic properties and pharmacodynamic effects of intranasal PT- J Impot Res 2012; 24: 49-60. 141, a melanocortin receptor agonist, in healthy males and patients [176] Guagnini F, Ferazzini M, Grasso M, Blanco S, Croci T. Erectile with mild-to-moderate erectile dysfunction. Int J Impot Res 2004; properties of the Rho-kinase inhibitor SAR407899 in diabetic ani- 16: 51-9. mals and human isolated corpora cavernosa. J Transl Med 2012; [156] Kumar R, Nehra A. Central nervous system agents and erectile 10: 59. dysfunction. Urol Clin North Am 2011; 38: 165-73. [177] Buyukafsar K, Un I. Effects of the rho-kinase inhibitors, Y-27632 [157] Kaminetsky J, Zinner N, Gittleman M, Awerbach S, Fischkoff S. and fasudil, on the corpus cavernosum from diabetic mice. Eur J Phase IIb study of bremelanotide in the treatment of ED in non- Pharmacol 2003; 472: 235-8. diabetic males. Proceedings Of The American Urology Association [178] Cutler, N.R. PDE III inhibitors for treating sexual dysfunction. Annual Meeting; 19 - 24 May 2007; Anaheim, USA. US6541487B1 (2003). [158] Diamond LE, Earle DC, Garcia WD, Spana C. Coadministration of [179] Cutler, N.R. Use of quinolines and quinolones to treat male erectile low doses of intranasal PT-141, a melanocortin receptor agonist, dysfunction. US6303135B1 (2001). and sildenafil to men with erectile dysfunction results in an en- [180] Plettenburg, O., Lorenz, K., Weston, J., Loehn, M., Kleemann, H., hanced erectile response. Urology 2005; 65: 755-9. Duclos, O., Jeannot, F. Substituted isoquinolines and isoquinoli- [159] Harraz A, Shindel AW, Lue TF. Emerging gene and stem cell nones as Rho kinase inhibitors. US 8541449 (2013). therapies for the treatment of erectile dysfunction. Nat Rev Urol [181] Jain, N., Xu, J., Sui, Z. Quinoline derivatives as potassium ion 2010; 7: 143-52. channel openers. US7790895B2 (2010). [160] Yoshimura N, Kato R, Chancellor MB, Nelson JB, Glorioso JC. [182] Zhang, X., Li, X., Sui, Z. Benzopyran derivatives as potassium Gene therapy as future treatment of erectile dysfunction. Expert channel openers. US7812183B2 (2010). Opin Biol Ther 2010; 10: 1305-14. [183] Zhang, X., Sui, Z. Tricyclic dihydropyrazines as potassium channel [161] Bakircioglu ME, Lin CS, Fan P, Sievert KD, Kan YW, Lue TF. openers. US7674793B2 (2010). The effect of adeno-associated virus mediated brain derived neu- [184] Cutler, N.R. Use of cilostazol for treatment of sexual dysfunction. rotrophic factor in an animal model of neurogenic impotence. J US6187790B1 (2001). Urol 2001; 165: 2103-9. [185] Norfor Allerton, C.M., Cook, A.S., Hepworth, D., Miller, D.C. [162] Melman A, Bar-Chama N, McCullough A, Davies K, Christ G. New amino derivatives and their use as pharmaceuticals. hMaxi-K gene transfer in males with erectile dysfunction: Results US0005354A1 (2009). of the first human trial. Hum Gene Ther 2006; 17: 1165-76. [186] Sharma, S., Shadiack, A.M., Yang, W., Rajpurohit, R. Metallopep- [163] Vaegler M, Lenis AT, Daum L, Amend B, Stenzl A, Damaser MS, tide compositions for treatment of sexual dysfunctions. US0164914 et al. Stem cell therapy for voiding and erectile dysfunction. Nat (2005). Rev Urol 2012; Jun 19. doi: 10.1038/nrurol.2012.111. [187] Sharma, S.D., Shi, Y., Wu, Z., Rajpurohit, R. Peptidomimetics of [164] Zhang H, Albersen M, Jin X, Lin G. Stem cells: Novel players in biologically active metallopeptides. US7807678B2 (2010). the treatment of erectile dysfunction. Asian J Androl 2012; 14: [188] Lee, K., Lee, S.D., Moon, S.P., Ahn, I.A., Choi, S.P., Lee, H.H., 145-55. Shim, D.S., Chung, S.Y., Lee, H.M. EP20090826254 (2013). Treatments of Neurogenic ED Recent Patents on CNS Drug Discovery, 2014, Vol. 9, No. 1 53

[189] Eisinger, M., Fitzpatrick, L.J., Lee, D.H., Pan, K., Plata-Salaman, [192] Van, Z.M., Golebiowski, A., Ji, M.K., Whitehouse, D., Ryder, T., C., Reitz, A.B., Smith-Swintosky, V.L., Zhao, B. 1,2,4- Beckett, R.P. Inhibitors of arginase and their therapeutic applica- thiadiazolium derivatives as melanocortin receptor modulators. tions. WO2013059437A1 (2013). US8501791 (2010). [193] Fossel, E.T. Topical delivery of arginine of cause beneficial effects. [190] Sharma, S.D., Shadiack, A.M., Rajpurohit, R., Yang, W. Peptide US7914814 (2011). compositions for treatment of sexual dysfunction. US7795378B2 [194] Carney, D.H., Olszewska-Pazdrak, B., Fossum, T.W. Method of (2010). treating endothelial dysfunction. US20130130978A1 (2013). [191] Shi, Y., Sharma, S.D., Yang, W., Chen, X. Melanocortin receptor- [195] Calabrò RS, Polimeni G, Bramanti P. Current and future therapies specific peptides for treatment of female sexual dysfunction. of erectile dysfunction in neurological disorders. Recent Pat CNS US20130288987A1 (2013). Drug Discov 2011; 6: 48-64.