Emerging drugs for the treatment of erectile dysfunction

Expert Opinion on Emerging Drugs

Volumn 20, Issue 2, 2015, Pages 263-275

  Peak, Taylor C ^a   Yafi, Faysal A ^a   Sangkum, Premsant ^a   Hellstrom, Wayne Jg ^a  

^a TULANE UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Clavulanic acid; Dopaminergic agonists; Erectile dysfunction; Intracavernosal injection therapy; l arginine; Lodenafil carbonate; Maxi K channel activators; Melanocortin receptor agonists; Mirodenafil; Phosphodiesterase 5 inhibitors; Rho kinase inhibitors; Sildenafil orodispersable tablet; SLx 2101; Soluble guanylate cyclase; Udenafil; Yohimbine

Indexed keywords

2 [[4 (2 PYRIDINYL) 1 PIPERAZINYL]METHYL] 1H BENZIMIDAZOLE; ABT 670; AGENTS ACTING ON THE GENITAL SYSTEM; BREMELANOTIDE; CLAVULANIC ACID; DOPAMINE RECEPTOR; FASUDIL; LARGE CONDUCTANCE CALCIUM ACTIVATED POTASSIUM CHANNEL; LODENAFIL; MELANOTAN II; MIRODENAFIL; NELOCIGUAT; NS 11021; PHOSPHODIESTERASE V INHIBITOR; SAR 407899; SILDENAFIL; SLX 2101; UDENAFIL; UNCLASSIFIED DRUG;

ERECTILE DYSFUNCTION; HEALTH CARE NEED; HUMAN; MALE; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); REVIEW; SMOOTH MUSCLE CONTRACTILITY; SMOOTH MUSCLE CONTRACTION; SMOOTH MUSCLE RELAXATION; ANIMAL; DRUG DESIGN; DRUG EFFECTS; MOLECULARLY TARGETED THERAPY; PATHOPHYSIOLOGY; PENIS ERECTION; PHYSIOLOGY;

ANIMALS; DRUG DESIGN; ERECTILE DYSFUNCTION; HUMANS; MALE; MOLECULAR TARGETED THERAPY; PENILE ERECTION; PHOSPHODIESTERASE 5 INHIBITORS;

EID: 84930015224     PISSN: 14728214     EISSN: 17447623     Source Type: Journal    
DOI: 10.1517/14728214.2015.1021682     Document Type: Review

References (94)

1. Montorsi F, ADaikan G, Becher E, et al. Summary of the recommenDations on sexual dysfunctions in men. J Sex Med 2010;7(11):3572-88
2. Lue TF. Erectile dysfunction. N Engl J Med 2000;342(24):1802-13
3. Porst H, Sharlip ID. History and epiDemiology of male sexual dysfunction. In: Porst H, Buvat J, editors the StanDards Committee of the International Society for Sexual Medicine. StanDards Committee of the International Society for Sexual Medicine. BLackwePublishing Ltd; Oxford, UK: 2006
4. Braun M, Wassmer G, Klotz T, et al. EpiDemiology of erectile dysfunction: results of the Cologne Male Survey. Int J Impot Res 2000;12(6):305-11
5. Kumamoto Y, Tsukamoto T, Satoh T, et al. EpiDemiological study on aging changes of sexual activity in japanese men and women. Aging Male 2000;3(suppl 1):9
6. Cronenwett J, Johnston K. Erectile dysfunction. In: Cronenwett JL, Wayne Johnston K, editors. Rutherfords vascul surgery. 8th edition. SaunDers; PhiLaDelphia, PA: 2014. p. 1208-20
7. Eardley I, Donatucci C, Corbin J, et al. Pharmacotherapy for erectile dysfunction. J Sex Med 2010;7(1 Pt 2):524-40
8. Hatzimouratidis K, Amar E, Eardley I, et al. GuiDelines on male sexual dysfunction: erectile dysfunction and premature ejacuLation. Eur Urol 2010;57(5):804-14
9. Rosen RC, Kostis JB. Overview of phosphodiesterase 5 inhibition in erectile dysfunction. Am J Cardiol 2003;92:9a-9m-18m
10. Berner MM, Kriston L, Harms A. Efficacy of PDE-5-inhibitors for erectile dysfunction. A comparative meta-Analysis of fixed-dose regimen randomized controlled trials administering the International InDex of Erectile Function in broad-spectrum popuLations. Int J Impot Res 2006;18(3):229-35
11. Coward RM, Carson CC. TaDaLafil in the treatment of erectile dysfunction ther Clin Risk Manag 2008;4(6):1315-30
12. MochiDa H, Yano K, Inoue H, et al. AVanafil, a highly selective phosphodiesterase type 5 inhibitor for erectile dysfunction, shows good safety profiles for retinal function and hemodynamics in anesthetized dogs. J Urol 2013;190(2):799-806
13. Goldstein I, Jones LA, Belkoff LH, et al. AVanafil for the treatment of erectile dysfunction: A multicenter, randomized, double-blind study in men with diabetes mellitus. Mayo Clin Proc 2012;87(9):843-52
14. Morales AM, CasilLas M, Turbi C. Patients preference in the treatment of erectile dysfunction: A critical review of the literature. Int J Impot Res 2011;23(1):1-8
15. Hanchanale V, Eardley I. Alprostadil for the treatment of impotence. Expert Opin Pharmacother 2014;15(3):421-8
16. Godschalk MF, Chen J, Katz PG, et al. Treatment of erectile failure with prostagLandin E1: A double-blind, pLacebo-controlled, dose-response study. J Urol 1994;151(6):1530-2
17. Porst H the rationale for prostagLandin E1 in erectile failure: A survey of worldwiDe experience. J Urol 1996;155(3):802-15
18. Heaton JP, Lording D, Liu SN, et al. Intracavernosal alprostadil is effective for the treatment of erectile dysfunction in diabetic men. Int J Impot Res 2001;13(6):317-21
19. BelLa AJ, Brock GB. Intracavernous pharmacotherapy for erectile dysfunction. Endocrine 2004;23(2-3):149-55
20. Sandhu D, Curless E, Dean J, et al. A double blind, pLacebo controlled study of intracavernosal vasoactive intestinal polypeptiDe and phenotoLamine mesyLate in a novel auto-injector for the treatment of non-psychogenic erectile dysfunction. Int J Impot Res 1999;11(2):91-7
21. Dinsmore WW, GingeC, Hackett G, et al. Treating men with predominantly nonpsychogenic erectile dysfunction with intracavernosal vasoactive intestinal polypeptiDe and phentoLamine mesyLate in a novel auto-injector system: A multicentre double-blind pLacebo-controlled study. BJU Int 1999;83(3):274-9
22. Dinsmore WW, Wyllie MG. Vasoactive intestinal polypeptiDe/phentoLamine for intracavernosal injection in erectile dysfunction. BJU Int 2008;102(8):933-7
23. Bechara A, Casabe A, Cheliz G, et al. ProstagLandin E1 versus mixture of prostagLandin E1, papaverine and phentoLamine in nonresponDers to high papaverine plus phentoLamine doses. J Urol 1996;155(3):913-14
24. Bechara A, Casabe A, Cheliz G, et al. Comparative study of papaverine plus phentoLamine versus prostagLandin E1 in erectile dysfunction. J Urol 1997;157(6):2132-4
25. Fulgham PF, Cochran JS, Denman JL, et al. Disappointing initial results with transurethral alprostadil for erectile dysfunction in a urology practice setting. J Urol 1998;160(6 Pt 1):2041-6
26. Shabsigh R, Padma-Nathan H, Gittleman M, et al. Intracavernous alprostadil alfaDex is more efficacious, better tolerated, and preferred over intraurethral alprostadil plus optional actis: A comparative, randomized, crossover, multicenter study. Urology 2000;55(1):109-13
27. Filippi S, Luconi M, Granchi S, et al. Endothelium-DepenDency of yohimbineinduced corpus cavernosum reLaxation. Int J Impot Res 2002;14(4):295-307
28. Ernst E, Pittler MH. Yohimbine for erectile dysfunction: A systematic review and meta-Analysis of randomized clinical trials. J Urol 1998;159(2):433-6
29. LedDa A, Belcaro G, Cesarone MR, et al. Investigation of a complex pLant extract for mild to moDerate erectile dysfunction in a randomized, double-blind, pLacebocontrolled, parallel-Arm study. BJU Int 2010;106(7):1030-3
30. Chen J, Wollman Y, Chernichovsky T, et al. Effect of oral administration of high-dose nitric oxiDe donor L-Arginine in men with organic erectile dysfunction: results of a double-blind, randomized, pLacebo-controlled study. BJU Int 1999;83(3):269-73
31. Maclennan KM, Boshier A, Wilton LV, Shakir SA. Examination of the safety and use of apomorphine prescribed in general practice in EngLand as a treatment for erectile dysfunction. BJU Int 2006;98(1):125-31
32. Sopko NA, Hannan JL, BivaLacqua TJ. UnDerstanding and targeting the Rho kinase pathway in erectile dysfunction. Nat Rev Urol 2014;11(11):622-8
33. Costa C, Soares R, CasteLa A, et al. Increased endothelial apoptotic ceDensity in human diabetic erectile tissue-comparison with clinical Data. J Sex Med 2009;6(3):826-35
34. Magheli A, Burnett AL. Erectile dysfunction following prostatectomy: prevention and treatment. Nat Rev Urol 2009;6(8):415-27
35. MulhaJP, Morgentaler A. Penile rehabilitation should become the norm for radical prostatectomy patients. J Sex Med 2007;4(3):538-43
36. Traish AM, Munarriz R, OConn L, et al. Effects of medical or surgical castration on erectile function in an animal moDel. J Androl 2003;24(3):381-7
37. HuEM, Eaton RC, Markowski VP, et al. Opposite influence of medial preoptic D1 and D2 receptors on genital reflexes: implications for copuLation. Life Sci 1992;51(22):1705-13
38. Melis MR, Stancampiano R, Gessa GL, et al. Prevention by morphine of apomorphine-And oxytocin-induced penile erection and yawning: site of action in the brain. Neuropsychopharmacology 1992;6(1):17-21
39. De Groat WC, Booth A. Neural control of penile erection. In: Maggi CA, editor the autonomic nervous system. Harwood, London; 1993. p. 465-513
40. AnDersson KE, Wagner G. Physiology of penile erection. Physiol Rev 1995;75(1):191-236
41. Gelez H, Poirier S, Facchinetti P, et al. Neuroanatomical eviDence for a role of central meLanocortin-4 receptors and oxytocin in the efferent control of the roDent clitoris and vagina. J Sex Med 2010;7(6):2056-67
42. Van Der Ploeg LH, Martin WJ, Howard AD, et al. A role for the meLanocortin 4 receptor in sexual function. Proc Natl Acad Sci USA 2002;99(17):11381-6
43. Dean RC, Lue TF. Physiology of penile erection and pathophysiology of erectile dysfunction. Urol Clin North Am 2005;32(4):379-95, v
44. Lue TF. Physiology of penile erection and pathophysiology of erectile dysfunction. In: Wein AJ, Kavoussi LR, Novick AC, Partin AW, et al. Campbell-Walsh Urology. 10th editon. WB SaunDers Co; PhiLaDelphia: 2012. p. 688-720
45. Dai Y, Zhang Y, Phatarpekar P, et al. ADenosine signaling, priapism and novel therapies. J Sex Med 2009;6(Suppl 3):292-301
46. Johnson DA, Akamine P, Radzio-Andzelm E, et al. Dynamics of cAMP-DepenDent protein kinase. Chem Rev 2001;101(8):2243-70
47. Simonsen U, Prieto D, HernanDez M, et al. Adrenoceptor-mediated reguLation of the contractility in horse penile resistance arteries. J Vasc Res 1997;34(2):90-102
48. Okon EB, Szado T, Laher I, et al. Augmented contractile response of vascuLar smooth muscle in a diabetic mouse moDel. J Vasc Res 2003;40(6):520-30
49. Rees RW, Ziessen T, Ralph DJ, et al. Human and rabbit cavernosal smooth muscle cells express Rho-kinase. Int J Impot Res 2002;14(1):1-7
50. Ito M, Nakano T, Erdodi F, et al. Myosin phosphatase: structure, reguLation and function. Mol CeBiochem 2004;259(1-2):197-209
51. Hamid SA, Bower HS, Baxter GF. Rho kinase activation pLays a major role as a mediator of irreversible injury in reperfused myocardium. Am J Physiol Heart Circ Physiol 2007;292(6):H2598-606
52. Large WA. Receptor-operated Ca2(+)-permeable nonselective cation channels in vascuLar smooth muscle: A physiologic perspective. J Cardiovasc Electrophysiol 2002;13(5):493-501
53. Fan SF, Brink PR, Melman A, et al. An analysis of the Maxi-K+ (KCa) channel in cultured human corporal smooth muscle cells. J Urol 1995;153(3 Pt 1):818-25
54. Christ GJ, Spray DC, Brink PR. Characterization of K currents in cultured human corporal smooth muscle cells. J Androl 1993;14(5):319-28
55. BivaLacqua TJ, Hellstrom WJ. Potential application of gene therapy for the treatment of erectile dysfunction. J Androl 2001;22(2):183-90
56. Melman A, Bar-Chama N, McCullough A, et al. hMaxi-K gene transfer in males with erectile dysfunction: results of the first human trial. Hum Gene Ther 2006;17(12):1165-76
57. Damle B, Duczynski G, Jeffers BW, et al. Pharmacokinetics of a novel orodispersible tablet of silDenafil in healthy subjects. Clin Ther 2014;36(2):236-44
58. Doh H, Shin CY, Son M, et al. Mechanism of erectogenic effect of the selective phosphodiesterase type 5 inhibitor, DA-8159. Arch Pharm Res 2002;25(6):873-8
59. Moon du G, Yang DY, Lee CH, et al. A therapeutic confirmatory study to assess the safety and efficacy of ZyDena (uDenafil) for the treatment of erectile dysfunction in male patients with diabetes mellitus. J Sex Med 2011;8(7):2048-61
60. Paick JS, Kim SW, Park YK, et al the efficacy and safety of uDenafil [ZyDena] for the treatment of erectile dysfunction in hypertensive men taking concomitant antihypertensive agents. J Sex Med 2009;6(11):3166-76
61. Chung BH, Lee JY, Lee SH, et al. Safety and efficacy of the simultaneous administration of uDenafil and an alphablocker in men with erectile dysfunction concomitant with BPH/LUTS. Int J Impot Res 2009;21(2):122-8
62. Zhao C, Kim SW, Yang DY, et al. Efficacy and safety of once-Daily dosing of uDenafil in the treatment of erectile dysfunction: results of a multicenter, randomized, double-blind, pLacebocontrolled trial. Eur Urol 2011;60(2):380-7
63. Lee J, Yoo HH, Rhim KJ, et al. Metabolism and excretion of 5-ethyl-2-{5-[4-(2-hydroxyethyl)piperazine-1-sulfonyl]-2-propoxyphenyl}-7-propyl-3 ,5-dihydropyrrolo[3 ,2-d]-pyrimidin-4-one (SK3530) in rats. Rapid Commun Mass Spectrom 2007;21(7):1139-49
64. Paick JS, Ahn TY, Choi HK, et al. Efficacy and safety of miroDenafil, a new oral phosphodiesterase type 5 inhibitor, for treatment of erectile dysfunction. J Sex Med 2008;5(11):2672-80
65. Lee JY, Cho SY, Oh CY, et al. Efficacy and safety of combination therapy with miroDenafil and alpha1-blocker for benign prostatic hyperpLasia-induced lower urinary tract symptoms accompanied by erectile dysfunction: A multicenter, open-Label, prospective study. Int J Impot Res 2011;23(6):249-56
66. Glina S, Toscano I, Gomatzky C, et al. Efficacy and tolerability of loDenafil carbonate for oral therapy in erectile dysfunction: A phase II clinical trial. J Sex Med 2009;6(2):553-7
67. Glina S, Fonseca GN, Bertero EB, et al. Eficacy and tolerability of loDenafil carbonate for oral therapy of erectile dysfunction: A phase III clinical trial. J Sex Med 2010;7(5):1928-36
68. Smith WB, McCaslin IR, Gokce A, et al. PDE5 inhibitors: consiDerations for preference and long-term adherence. Int J Clin Pract 2013;67(8):768-80
69. Sweetnam P, CampbeS, Grogan M, et al. SLx-2101, a novel long-Acting phosphodiesterase-5 (PDE5) inhibitor for erectile dysfunction: in vivo and in vitro studies [abstract no. 51]. J Sex Med 2006;3(suppl):29-30
70. SLx-2101; Pharmaprojects-copyright to citeline drug intelligence (an informa business
71. Wessells H, Levine N, Hadley ME, et al. MeLanocortin receptor agonists, penile erection, and sexual motivation: human studies with MeLanotan II. Int J Impot Res 2000;12(Suppl 4):S74-9
72. Diamond LE, Earle DC, Rosen RC, et al. Double-blind, pLacebo-controlled evaluation of the safety, pharmacokinetic properties and pharmacodynamic effects of intranasal PT-141, a meLanocortin receptor agonist, in healthy males and patients with mild-to-moDerate erectile dysfunction. Int J Impot Res 2004;16(1):51-9
73. Hellstrom W, Gittelman M, Zinner N, et al. Randomized, double-blind, pLacebo-controlled, at-home study to evaluate the efficacy and safety of intranasal bremeLanotiDe in men with erectile dysfunction with and without diabetes mellitus [abstract]. 9th Congress of the European Society for Sexual Medicine; Vienna, Austria; J Sex Med 2006. p. 117
74. Safarinejad MR, Hosseini SY. Salvage of silDenafil failures with bremeLanotiDe: A randomized, double-blind, pLacebo controlled study. J Urol 2008;179(3):1066-71
75. Diamond LE, Earle DC, Garcia WD, et al. Co-Administration of low doses of intranasal PT-141, a meLanocortin receptor agonist, and silDenafil to men with erectile dysfunction results in an enhanced erectile response. Urology 2005;65(4):755-9
76. Cowart M, Latshaw SP, Bhatia P, et al. Discovery of 2-(4-pyridin-2-ylpiperazin-1-ylmethyl)-1H-benzimiDazole (ABT-724), a dopaminergic agent with a novel moDe of action for the potential treatment of erectile dysfunction. J Med Chem 2004;47(15):3853-64
77. Brioni JD, MoreLand RB, Cowart M, et al. Activation of dopamine D4 receptors by ABT-724 induces penile erection in rats. Proc Natl Acad Sci USA 2004;101(17):6758-63
78. Patel MV, KoLasa T, MorteK, et al. Discovery of 3-methyl-N-(1-oxy-3 ,4 ,5 ,6-tetrahydro-2H-[2 ,4-bipyridine]-1-ylmethyl)benzam iDe (ABT-670), an orally bioavaiLable dopamine D4 agonist for the treatment of erectile dysfunction. J Med Chem 2006;49(25):7450-65
79. Chan JS, Kim DJ, Ahn CH, et al. CLavuLanic acid stimuLates sexual behaviour in male rats. Eur J Pharmacol 2009;609(1-3):69-73
80. Rexahn Pharmaceuticals, Inc. Efficacy Study of RX-10100 to Treat Erectile Dysfunction (ED). National Library ofMedicine (US). ClinicalTrials.gov; BethesDa (MD): 2009
81. Oudot A, Behr-Roussel D, Poirier S, et al. Combination of BAY 60-4552 and varDenafil exerts proerectile facilitator effects in rats with cavernous nerve injury: A proof of concept study for the treatment of phosphodiesterase type 5 inhibitor failure. Eur Urol 2011;60(5):1020-6
82. Albersen M, Linsen L, Tinel H, et al. Synergistic effects of BAY 60-4552 and varDenafil on reLaxation of corpus cavernosum tissue of patients with erectile dysfunction and clinical phosphodiesterase type 5 inhibitor failure. J Sex Med 2013;10(5):1268-77
83. Bayer Healthcare AG. A prospective, randomized, double-blind, doubledummy, pLaceboand active controlled, multicenter study assessing the efficacy and safety of the combination BAY 60 4552/varDenafil compared to varDenafil (20 mg) for the treatment of erectile dysfunction not sufficiently responsive to stanDard therapy with PDE5 inhibitors. National Library of Medicine (US), ClinicalTrials.gov; BethesDa (MD): 2014
84. Buyukafsar K, Un I. Effects of the Rhokinase inhibitors, Y-27632 and fasudil, on the corpus cavernosum from diabetic mice. Eur J Pharmacol 2003;472(3):235-8
85. Li WJ, Park K, Paick JS, et al. Chronic treatment with an oral rho-kinase inhibitor restores erectile function by suppressing corporal apoptosis in diabetic rats. J Sex Med 2011;8(2):400-10
86. Saito A, Inoue M, Kon H, et al. Effectiveness of intraarterial administration of fasudil hydrochloriDe for preventing symptomatic vasospasm after subarachnoid hemorrhage. Acta Neurochir Suppl 2015;120:297-301
87. Otsuka T, Ibuki C, Suzuki T, et al. Administration of the Rho-kinase inhibitor, fasudil, following nitroglycerin additionally diLates the site of coronary spasm in patients with vasospastic angina. Coron Artery Dis 2008;19(2):105-10
88. Lasker GF, Maley JH, Kadowitz PJ. A review of the pathophysiology and novel treatments for erectile dysfunction. Adv Pharmacol Sci 2010;2010; pii: 730861
89. Guagnini F, Ferazzini M, Grasso M, et al. Erectile properties of the Rhokinase inhibitor SAR407899 in diabetic animals and human isoLated corpora cavernosa. J Transl Med 2012;10:59
90. Sanofi-Avenis. Randomized, doubleblind, pLacebo and active controlled study of the activity of SAR407899 single-dose on the ability to increase duration of penile rigidity, unDer experimental condition, in patients with mild to moDerate erectile dysfunction. National Library of Medicine: ClinicalTrials.gov, BethesDa (MD; 2009
91. Bentzen BH, Olesen SP, Ronn LC, et al. BK channel activators and their therapeutic perspectives. Front Physiol 2014;5:389
92. Kun A, Matchkov VV, Stankevicius E, et al. NS11021, a novel opener of Largeconductance Ca(2+)-Activated K(+) channels, enhances erectile responses in rats. Br J Pharmacol 2009;158(6):1465-76
93. Kiraly I, Pataricza J, Bajory Z, et al. Involvement of Large-conductance Ca(2+)-Activated K(+) channels in both nitric oxiDe and endothelium-Derived hyperpoLarization-type reLaxation in human penile smaarteries. Basic Clin Pharmacol Toxicol 2013;113(1):19-24
94. Bang WJ, Oh CY, Yoo C, et al. Efficacy and saftey of the simuLatneous administration of miroDenafil and an alpha-blocker in men with BPH-LUTS: A multicenter open-Label prospective study. In J Impot Res 2013;25(4):149-54