FR226807: a potent and selective phosphodiesterase type 5 inhibitor.
We describe the pharmacological characteristics of a novel phosphodiesterase type 5 inhibitor FR226807, N-(3,4-dimethoxybenzyl)-2-[[(1R)-2-hydroxy-1-methylethyl]amino]-5-nitrobenzamide. FR226807 inhibited phosphodiesterase type 5 isolated from human platelets with an IC(50) value of 1.1 nM. FR226807 also inhibited phosphodiesterase type 6 with an IC(50) of 20 nM; however, the IC(50) value for phosphodiesterase type 6 was 18-fold higher than that for phosphodiesterase type 5. The IC(50) values of FR226807 for other phosphodiesterases (phosphodiesterase type 1, phosphodiesterase type 2, phosphodiesterase type 3, and phosphodiesterase type 4) were 1000-fold higher than that for phosphodiesterase type 5. FR226807 increased the cyclic guanosine monophosphate (cGMP) content in corpus cavernosum isolated from rabbit, an effect associated with relaxation of the muscle. FR226807 enhanced the relaxation response induced by electrical field stimulation of corpus cavernosum isolated from the rabbit. In an anesthetized dog model for the evaluation of erectile function, intravenous administration of FR226807 prolonged the time to return to 75% of maximal intracavernosal pressure after cessation of electrical stimulation of the pelvic nerve. In summary, FR226807 is a potent and highly selective phosphodiesterase type 5 inhibitor with an augmentative effect on penile erection and will be useful for the treatment of erectile dysfunction.
Hosogai
N
N
Medical Biology Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., 2-1-6, Yodogawa, Kashima, Osaka 532-8514, Japan. naomi_hosogai@po.fujisawa.co.jp
Hamada
K
K
Tomita
M
M
Nagashima
A
A
Takahashi
T
T
Sekizawa
T
T
Mizutani
T
T
Urano
Y
Y
Kuroda
A
A
Sawada
K
K
Ozaki
T
T
Seki
J
J
Goto
T
T
D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D006152:Cyclic GMP / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D010413:Penis / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000187:drug effects* / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D011312:Pressure; D011687:Purines; D011817:Rabbits; D000068677:Sildenafil Citrate; D013450:Sulfones; D013997:Time Factors
D001549:Benzamides; D007527:Isoenzymes; C442640:N-(3,4-dimethoxybenzyl)-2-((2-hydroxy-1-methylethyl)amino)-5-nitrobenzamide; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human; D006152:Cyclic GMP