Avanafil, a potent and highly selective phosphodiesterase-5 inhibitor for erectile dysfunction.
OBJECTIVE
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.


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.
Advanced Medical Research Laboratories, Mitsubishi Tanabe Pharma Corp., Yokohama, Japan.
Jun
J
Kotera
Hideki
H
Mochida
Hirotaka
H
Inoue
Tsunehisa
T
Noto
Kotomi
K
Fujishige
Takashi
T
Sasaki
Tamaki
T
Kobayashi
Koki
K
Kojima
Shiyin
S
Yee
Yasuhiro
Y
Yamada
Kohei
K
Kikkawa
Kenji
K
Omori
D000818:Animals; D002243:Carbolines / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D007172:Erectile Dysfunction / Q000503:physiopathology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007262:Infusions, Intravenous; D008297:Male; D010410:Penile Erection / Q000187:drug effects; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology*; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology; D000068581:Tadalafil; D014227:Triazines / Q000494:pharmacology; D000069058:Vardenafil Dihydrochloride
D002243:Carbolines; D007093:Imidazoles; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D011743:Pyrimidines; D013450:Sulfones; D014227:Triazines; D000069058:Vardenafil Dihydrochloride; D000068581:Tadalafil; D000068677:Sildenafil Citrate; C553414:avanafil