FR-226807

Our recent study suggests that there is a reciprocal mechanism to maintain cGMP content, via both a decrease in cGMP degradation (decrease in cGMP-phosphodiesterase activity) and an increase in synthesis of cGMP (increase in guanylate cyclase activity) in the kidney of cyclosporin A-treated rats. We undertook this study to clarify the role of cGMP-phosphodiesterase in cyclosporin A nephrotoxicity by evaluating N-(3,4-dimethoxybenzyl)-2-[[(1R)-2-hydroxy-1-methylethyl]amino]-5-nitrobenzamide (FR226807), a phosphodiesterase type 5 inhibitor, in an animal model. Male spontaneous hypertensive rats (SHR) were treated with cyclosporin A (50 mg/kg) for 2 weeks or with cyclosporin A and FR226807 (3.2 mg/kg or 10 mg/kg) for 2 weeks. Cyclosporin A-treated rats showed renal dysfunction and histological change compared with vehicle-treated rats. Administration of FR226807 improved the renal dysfunction (increase in serum creatinine and fractional excretion of sodium, and decrease in creatinine clearance) as well as the pathological changes (tubular vacuolization) induced by cyclosporin A in SHR. At the molecular level, administration of FR226807 resulted in a further increase in cGMP content in the kidney, aorta and platelets from cyclosporin A-treated rats. Our present study demonstrates that cGMP-phosphodiesterase plays an important role in the cyclosporin A nephrotoxicity and also suggests that further inhibition of cGMP-phosphodiesterase is a potential pharmacological target for preventing cyclosporin A nephrotoxicity.

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.