Avanafil, 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, Kenji Omori

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)668-674
Number of pages7
JournalJournal of Urology
Volume188
Issue number2
DOIs
StatePublished - Aug 2012
Externally publishedYes

Keywords

  • 4-((3-chloro-4-methoxybenzyl)amino)-2-(2- (hydroxymethyl)-1-pyrrolidinyl)-N-(2-pyrimidinylmethyl)-5-pyrimidinecarboxamide
  • erectile dysfunction
  • penis
  • pharmacology
  • phosphodiesterase inhibitors

ASJC Scopus subject areas

  • Urology

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