Portal de Periódicos da CAPES

Avanafil, a Potent and Highly Selective Phosphodiesterase-5 Inhibitor for Erectile Dysfunction

2012; Lippincott Williams & Wilkins; Volume: 188; Issue: 2 Linguagem: Inglês

10.1016/j.juro.2012.03.115

1527-3792

Jun Kotera, Hideki Mochida, Hirotaka Inoue, Tsunehisa Noto, Kotomi Fujishige, Takashi Sasaki, K. Tamaki, Koki Kojima, Shiyin Yee, Yasuhiro Yamada, Kohei Kikkawa, Kenji Omori,

Migraine and Headache Studies

No AccessJournal of UrologyInvestigative Urology1 Aug 2012Avanafil, a Potent and Highly Selective Phosphodiesterase-5 Inhibitor for Erectile Dysfunction Jun Kotera, Hideki Mochida, Hirotaka Inoue, Tsunehisa Noto, Kotomi Fujishige, Takashi Sasaki, Tamaki Kobayashi, Koki Kojima, Shiyin Yee, Yasuhiro Yamada, Kohei Kikkawa, and Kenji Omori Jun KoteraJun Kotera Advanced Medical Research Laboratories, Mitsubishi Tanabe Pharma Corp., Yokohama, Japan , Hideki MochidaHideki Mochida Pharmacology Research Laboratories II, Mitsubishi Tanabe Pharma Corp., Saitama, Japan , Hirotaka InoueHirotaka Inoue Pharmacology Research Laboratories II, Mitsubishi Tanabe Pharma Corp., Saitama, Japan , Tsunehisa NotoTsunehisa Noto Pharmacology Research Laboratories II, Mitsubishi Tanabe Pharma Corp., Saitama, Japan , Kotomi FujishigeKotomi Fujishige Advanced Medical Research Laboratories, Mitsubishi Tanabe Pharma Corp., Yokohama, Japan , Takashi SasakiTakashi Sasaki Advanced Medical Research Laboratories, Mitsubishi Tanabe Pharma Corp., Yokohama, Japan , Tamaki KobayashiTamaki Kobayashi Advanced Medical Research Laboratories, Mitsubishi Tanabe Pharma Corp., Yokohama, Japan , Koki KojimaKoki Kojima Pharmacology Research Laboratories II, Mitsubishi Tanabe Pharma Corp., Saitama, Japan , Shiyin YeeShiyin Yee Vivus, Inc., Mountain View, California , Yasuhiro YamadaYasuhiro Yamada DMPK Research Laboratories, Mitsubishi Tanabe Pharma Corp., Saitama, Japan , Kohei KikkawaKohei Kikkawa DMPK Research Laboratories, Mitsubishi Tanabe Pharma Corp., Saitama, Japan , and Kenji OmoriKenji Omori Advanced Medical Research Laboratories, Mitsubishi Tanabe Pharma Corp., Yokohama, Japan View All Author Informationhttps://doi.org/10.1016/j.juro.2012.03.115AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract Purpose: We investigated the in vitro inhibitory effects of avanafil, a novel, potent inhibitor of phosphodiesterase-5, on 11 phosphodiesterases. We also studied its potentiation of penile tumescence in dogs. Materials and Methods: Phosphodiesterase assay was done with the 4 phosphodiesterase-5 inhibitors avanafil, sildenafil, vardenafil and tadalafil using 11 phosphodiesterase isozymes. In anesthetized dogs the pelvic nerve was repeatedly stimulated to evoke tumescence. Intracavernous pressure was measured after avanafil or sildenafil administration. Results: Avanafil specifically inhibited phosphodiesterase-5 activity at a 50% inhibitory concentration of 5.2 nM. Avanafil showed higher selectivity (121-fold) against phosphodiesterase-6 than sildenafil and vardenafil (16 to 21-fold) and showed excellent selectivity (greater than 10,000-fold) against phosphodiesterase-1 compared with sildenafil (375-fold). Avanafil also had higher selectivity against phosphodiesterase-11 than tadalafil (greater than 19,000 vs 25-fold). Avanafil also showed excellent selectivity against all other phosphodiesterases. After intravenous administration in anesthetized dogs the 200% effective dose of avanafil and sildenafil on the penile tumescence was 37.5 and 34.6 μg/kg, respectively. After intraduodenal administration the 200% effective dose of avanafil and sildenafil on tumescence was 151.7 and 79.0 μg/kg at the peak time, respectively. Time to peak response with avanafil and sildenafil was 10 and 30 minutes, respectively, indicating a more rapid onset of avanafil. Conclusions: Avanafil has a favorable phosphodiesterase-5 selectivity profile compared to that of marketed phosphodiesterase-5 inhibitors. Avanafil shows excellent in vitro and in vivo potency, and fast onset of action for penile erection. Cumulative data suggest that avanafil has a promising pharmacological profile for erectile dysfunction. References 1 : Overview of PDEs and their regulation. Circ Res2007; 100: 309. Google Scholar 2 : Phosphodiesterase-5 molecular characteristics relating to structure, function, and regulation. In: Cyclic Nucletotide Phoshodiesterases in Health and Disease. Edited by . London: CRC Press2007: 131. chap 7. Google Scholar 3 : Cardiovascular effects of the 3 phosphodiesterase-5 inhibitors approved for the treatment of erectile dysfunction. Circulation2004; 110: 3149. Google Scholar 4 : A selective type V phosphodiesterase inhibitor, E4021, protects the development of right ventricular overload and medial thickening of pulmonary arteries in a rat model of pulmonary hypertension. Life Sci1996; 59: PL 371. Google Scholar 5 : Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy. Nat Med2005; 11: 214. Google Scholar 6 : Investigational noncardiovascular uses of phosphodiesterase-5 inhibitors. Expert Opin Pharmacother2011; 12: 2297. Google Scholar 7 : Characterization and effects of methyl-2-(4-aminophenyl)-1,2-dihydro-1-oxo-7-2-pyridinylmethoxy)-4-(3,4,5-trimethoxyphenyl)-3-isoquinoline carboxylate sulfate (T-1032), a novel potent inhibitor of cGMP-binding cGMP-specific phosphodiesterase (PDE5). Biochem Pharmacol2000; 60: 1333. Google Scholar 8 : Striatum- and testis-specific phosphodiesterase PDE10A: Isolation and characterization of a rat PDE10A. Eur J Biochem1999; 266: 1118. Google Scholar 9 : Identification of human PDE7B, a cAMP-specific phosphodiesterase. Biochem Biophys Res Commun2000; 271: 575. Google Scholar 10 : Comparison of enzymatic characterization and gene organization of cyclic nucleotide phosphodiesterase 8 family in humans. Cell Signal2003; 15: 565. Google Scholar 11 : Isolation and characterization of two novel phosphodiesterase PDE11A variants showing unique structure and tissue-specific expression. J Biol Chem2000; 275: 31469. Google Scholar 12 : Potentiation of penile tumescence by T-1032, a new potent and specific phosphodiesterase type V inhibitor, in dogs. J Pharmacol Exp Ther2000; 294: 870. Google Scholar 13 : Nitric oxide and cGMP: mediators of pelvic nerve-stimulated erection in dogs. Am J Physiol1993; 264: H419. Medline, Google Scholar 14 : A selective type V phosphodiesterase inhibitor, E4021, dilates porcine large coronary artery. J Pharmacol Exp Ther1995; 272: 825. Google Scholar 15 : Rabbit corpus cavernosum smooth muscle shows a different phosphodiesterase profile than human corpus cavernosum. J Urol2000; 164: 882. Link, Google Scholar 16 : Isoenzymes of cyclic nucleotide phosphodiesterase in the human aorta: characterization and the effects of E4021. Eur J Pharmacol1995; 284: 25. Google Scholar 17 : Antiplatelet and antiproliferative effects of SCH 51866, a novel type 1 and type 5 phosphodiesterase inhibitor. Cardiovasc Pharmacol1996; 28: 862. Google Scholar 18 : Phosphodiesterase 11 (PDE11) regulation of spermatozoa physiology. Int J Impot Res2005; 17: 216. Google Scholar 19 : Mechanism of erectogenic effect of the selective phosphodiesterase type 5 inhibitor, DA-8159. Arch Pharm Res2002; 25: 873. Google Scholar 20 : Tolerability and pharmacokinetics of avanafil, a phosphodiesterase type 5 inhibitor: a single- and multiple-dose, double-blind, randomized, placebo-controlled, dose-escalation study in healthy Korean male volunteers. Clin Ther2010; 32: 1178. Google Scholar 21 : Avanafil, a new rapid-onset phosphodiesterase 5 inhibitor for the treatment of erectile dysfunction. Expert Opin Investig Drugs2010; 19: 1427. Google Scholar © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetailsCited byHellstrom W, Kaminetsky J, Belkoff L, Goldstein I, Tursi J, Uy J, Peterson C, Bowden C and Day W (2015) Efficacy of Avanafil 15 Minutes after Dosing in Men with Erectile Dysfunction: A Randomized, Double-Blind, Placebo Controlled StudyJournal of Urology, VOL. 194, NO. 2, (485-492), Online publication date: 1-Aug-2015.Seftel A (2014) Re: Tadalafil Treatment had a Modest Effect on Endothelial Cell Damage and Repair Ability Markers in Men with Erectile Dysfunction and Vascular RiskJournal of Urology, VOL. 192, NO. 1, (179-180), Online publication date: 1-Jul-2014.Seftel A (2014) Re: Management of ED under the "Severe Distress" Criteria in the NHS: A Real-Life StudyJournal of Urology, VOL. 191, NO. 6, (1841-1842), Online publication date: 1-Jun-2014.Seftel A (2014) Re: Men with Diabetes May Require More Aggressive Treatment for Erectile DysfunctionJournal of Urology, VOL. 191, NO. 5, (1352-1353), Online publication date: 1-May-2014.Mochida H, Yano K, Inoue H, Yee S, Noto T and Kikkawa K (2013) Avanafil, a Highly Selective Phosphodiesterase Type 5 Inhibitor for Erectile Dysfunction, Shows Good Safety Profiles for Retinal Function and Hemodynamics in Anesthetized DogsJournal of Urology, VOL. 190, NO. 2, (799-806), Online publication date: 1-Aug-2013.Mulhall J, Burnett A, Wang R, McVary K, Moul J, Bowden C, DiDonato K, Shih W and Day W (2012) A Phase 3, Placebo Controlled Study of the Safety and Efficacy of Avanafil for the Treatment of Erectile Dysfunction After Nerve Sparing Radical ProstatectomyJournal of Urology, VOL. 189, NO. 6, (2229-2236), Online publication date: 1-Jun-2013. Volume 188Issue 2August 2012Page: 668-674 Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.Keywords4-((3-chloro-4-methoxybenzyl)amino)-2-(2-(hydroxymethyl)-1-pyrrolidinyl)-N-(2-pyrimidinylmethyl)-5-pyrimidinecarboxamidepeniserectile dysfunctionpharmacologyphosphodiesterase inhibitorsMetricsAuthor Information Jun Kotera Advanced Medical Research Laboratories, Mitsubishi Tanabe Pharma Corp., Yokohama, Japan More articles by this author Hideki Mochida Pharmacology Research Laboratories II, Mitsubishi Tanabe Pharma Corp., Saitama, Japan Financial interest and/or other relationship with Mitsubishi Tanabe Pharma Corp. More articles by this author Hirotaka Inoue Pharmacology Research Laboratories II, Mitsubishi Tanabe Pharma Corp., Saitama, Japan Financial interest and/or other relationship with Mitsubishi Tanabe Pharma Corp. More articles by this author Tsunehisa Noto Pharmacology Research Laboratories II, Mitsubishi Tanabe Pharma Corp., Saitama, Japan Financial interest and/or other relationship with Mitsubishi Tanabe Pharma Corp. More articles by this author Kotomi Fujishige Advanced Medical Research Laboratories, Mitsubishi Tanabe Pharma Corp., Yokohama, Japan Financial interest and/or other relationship with Mitsubishi Tanabe Pharma Corp. More articles by this author Takashi Sasaki Advanced Medical Research Laboratories, Mitsubishi Tanabe Pharma Corp., Yokohama, Japan Financial interest and/or other relationship with Mitsubishi Tanabe Pharma Corp. More articles by this author Tamaki Kobayashi Advanced Medical Research Laboratories, Mitsubishi Tanabe Pharma Corp., Yokohama, Japan Financial interest and/or other relationship with Mitsubishi Tanabe Pharma Corp. More articles by this author Koki Kojima Pharmacology Research Laboratories II, Mitsubishi Tanabe Pharma Corp., Saitama, Japan Financial interest and/or other relationship with Mitsubishi Tanabe Pharma Corp. More articles by this author Shiyin Yee Vivus, Inc., Mountain View, California Financial interest and/or other relationship with Shiyin Yee, Vivus Inc. More articles by this author Yasuhiro Yamada DMPK Research Laboratories, Mitsubishi Tanabe Pharma Corp., Saitama, Japan Financial interest and/or other relationship with Mitsubishi Tanabe Pharma Corp. More articles by this author Kohei Kikkawa DMPK Research Laboratories, Mitsubishi Tanabe Pharma Corp., Saitama, Japan Financial interest and/or other relationship with Mitsubishi Tanabe Pharma Corp. More articles by this author Kenji Omori Advanced Medical Research Laboratories, Mitsubishi Tanabe Pharma Corp., Yokohama, Japan Financial interest and/or other relationship with Mitsubishi Tanabe Pharma Corp. More articles by this author Expand All Advertisement PDF downloadLoading ...