|show drug details|
|visual field defect||0.0010|
|loss of hearing||0.0010|
|coronary artery disease||0.0010|
|transient global amnesia||0|
|liver function tests abnormal||0|
|abdominal pain upper||0|
|Ki: ||Kd:||Ic 50:||Ec50/Ic50:|
The phosphodiesterase inhibitory selectivity and the in vitro and in vivo potency of the new PDE5 inhibitor vardenafil.. I Saenz de Tejada; J Angulo; P Cuevas; A Fernßndez; I Moncada; A Allona; E Lledˇ; H G K÷rschen; U Niew÷hner; H Haning; E Pages; E Bischoff (2001) International journal of impotence research display abstract
We investigated the potency and the selectivity profile of vardenafil on phosphodiesterase (PDEs) enzymes, its ability to modify cGMP metabolism and cause relaxation of penile smooth muscle and its effect on erections in vivo under conditions of exogenous nitric oxide (NO) stimulation. PDE isozymes were extracted and purified from human platelets (PDE5) or bovine sources (PDEs 1, 2, 3, 4 and 6). The inhibition of these PDEs and of human recombinant PDEs by vardenafil was determined. The ability to potentiate NO-mediated relaxation and influence cGMP levels in human corpus cavernosum strips was measured in vitro, and erection-inducing activity was demonstrated in conscious rabbits after oral administration together with intravenous doses of sodium nitroprusside (SNP). The effects of vardenafil were compared with those of the well-recognized PDE5 inhibitor, sildenafil (values for sildenafil in brackets). Vardenafil specifically inhibited the hydrolysis of cGMP by PDE5 with an IC50 of 0.7 nM (6.6 nM). In contrast, the IC50 of vardenafil for PDE1 was 180 nM; for PDE6, 11 nM; for PDE2, PDE3 and PDE4, more than 1000 nM. Relative to PDE5, the ratios of the IC50 for PDE1 were 257 (60), for PDE6 16 (7.4). Vardenafil significantly enhanced the SNP-induced relaxation of human trabecular smooth muscle at 3 nM (10 nM). Vardenafil also significantly potentiated both ACh-induced and transmural electrical stimulation-induced relaxation of trabecular smooth muscle. The minimum concentration of vardenafil that significantly potentiated SNP-induced cGMP accumulation was 3 nM (30 nM). In vivo studies in rabbits showed that orally administered vardenafil dose-dependently potentiated erectile responses to intravenously administered SNP. The minimal effective dose that significantly potentiated erection was 0.1 mg/kg (1 mg/kg). The selectivity for PDE5, the potentiation of NO-induced relaxation and cGMP accumulation in human trabecular smooth muscle and the ability to enhance NO-induced erection in vivo indicate that vardenafil has the appropriate properties to be a potential compound for the treatment of erectile dysfunction. Vardenafil was more potent and selective than sildenafil on its inhibitory activity on PDE5.
Vardenafil: structural basis for higher potency over sildenafil in inhibiting cGMP-specific phosphodiesterase-5 (PDE5).. Jackie D Corbin; Alfreda Beasley; Mitsi A Blount; Sharron H Francis (2004) Neurochemistry international display abstract
Phosphodiesterase-5 (PDE5) inhibitors act by competing with the substrate, cGMP, for the catalytic site of the enzyme. Two commercialized PDE5 inhibitors, sildenafil and vardenafil, are being used to treat erectile dysfunction. These two compounds differ in the heterocyclic ring system used to mimic the purine ring of cGMP. They also differ in the substituent (ethyl/methyl) of a piperazine side chain. Although these are the only two structural differences, vardenafil has more than 20-fold greater potency than sildenafil for inhibiting purified PDE5. The molecular structural basis for the difference in potency of the two compounds was investigated by synthesizing an analog of sildenafil ("methyl-sildenafil") that contained the sildenafil ring system but with the appended ethyl group found in vardenafil, and an analog of vardenafil ("demethyl-vardenafil") that contained the vardenafil ring system but with the appended methyl group found in sildenafil. The IC50 of methyl-sildenafil for inhibiting PDE5 indicated that it was 64 times less potent than demethyl-vardenafil, which was similar to the finding that, based on IC50, sildenafil was 40 times less potent than vardenafil. Similarly, the EC50 of methyl-sildenafil for inhibiting [3H]vardenafil binding to PDE5 indicated that it was 84 times less potent than demethyl-vardenafil, while the EC50 for sildenafil indicated that it was 31 times less potent than vardenafil. It is concluded that the methyl/ethyl appended group on the piperazine moiety plays very little role in the difference in potency between sildenafil and vardenafil for inhibiting PDE5, whereas the differences in the ring systems play a critical role in higher potency of vardenafil over sildenafil.
Absence of clinically important HERG channel blockade by three compounds that inhibit phosphodiesterase 5--sildenafil, tadalafil, and vardenafil.. R Dustan Sarazan; William J CrumbJr; Charles M BeasleyJr; Jeffrey T Emmick; Kenneth M Ferguson; Christine A Strnat; Peter J Sausen (2004) European journal of pharmacology display abstract
Compounds that inhibit phosphodiesterase 5 (PDE5) have been developed for the treatment of erectile dysfunction. Because men with erectile dysfunction frequently have comorbid cardiovascular disease, they may have limited cardiac repolarization reserve and be at risk of arrhythmia if treated with medications that prolong ventricular repolarization. The human ether-a-go-go related gene (HERG) channel is important for repolarization in human myocardium and is a common target for drugs that prolong the QT interval. We studied the ability of three compounds that inhibit PDE5--sildenafil, tadalafil, and vardenafil--to block the HERG channel. Using a whole cell variant of the patch-clamp method, the HERG current was measured in a stably transfected human embryonic kidney cell line expressing the HERG channel. The compounds produced dose-dependent reductions in HERG current amplitude over a concentration range of 0.1 to 100 microM. The IC50 values were 12.8 microM for vardenafil and 33.3 microM for sildenafil. Because the maximum soluble concentration of tadalafil (100 microM) produced only a 50.9% inhibition of the HERG current amplitude, the IC50 value for tadalafil could not be determined with the Hill equation. Tadalafil had the weakest capacity to block the HERG channel, producing a 50.9% blockade at the maximum soluble concentration (100 microM), compared with 86.2% for vardenafil (100 microM) and 75.2% for sildenafil (100 microM). In conclusion, the concentrations of the PDE5 inhibitors required to evoke a 50% inhibition of the HERG current were well above reported therapeutic plasma concentrations of free and total compound. None of the three compounds was a potent blocker of the HERG channel.
Phosphodiesterase-5 isoforms: differential cyclic guanyl monophosphate binding and cyclic guanyl monophosphate catalytic activities, and inhibitory effects of sildenafil and vardenafil.. Guiting Lin; Zhong-Cheng Xin; Tom F Lue; Ching-Shwun Lin (2006) The Journal of urology display abstract
PURPOSE: We determined the differential cyclic guanyl monophosphate catalytic and cyclic guanyl monophosphate binding activity of phosphodiesterase-5 isoforms and the inhibitory effects of sildenafil (Pfizer, New York, New York) and vardenafil (Bayer Pharmaceutical Research, Wuppertal, Germany). MATERIALS AND METHODS: Coding sequences of the human phosphodiesterase-5 isoforms A1, A2 and A3 were cloned into pBlueBac4.5/V5-His (Invitrogen, Carlsbad, California), which allows the tagging of histidines at the carboxyl terminal of the expressed protein. Isoforms were expressed with the Bac-N-Blue baculoviral system and purified with the ProBond system. Expression clones were identified by polymerase chain reaction using vector and phosphodiesterase-5 specific primers. Purified proteins were verified by Western blotting. Purified proteins were analyzed for cyclic guanyl monophosphate catalytic and cyclic guanyl monophosphate binding activity, and used to determine the differential potencies of the phosphodiesterase-5 selective inhibitors sildenafil and vardenafil. RESULTS: Cloning and expression of phosphodiesterase-5A1 to A3 isoforms in the baculoviral system resulted in the isolation of purified isoform proteins. Mean cyclic guanyl monophosphate catalytic activity (K(m)) +/- SD was 4.76 +/- 0.37, 4.52 +/- 0.09 and 11.39 +/- 0.22 microM for A1 to A3, respectively. Mean cyclic guanyl monophosphate binding activity (K(d)) was 3.24 +/- 0.47, 1.95 +/- 0.60 and 1.70 +/- 0.47 microM for A1 to A3, respectively. Mean IC(50) of sildenafil against phosphodiesterase-5A1 to A3 was 1.20 +/- 0.34, 2.83 +/- 0.56 and 2.28 +/- 0.38 nM, respectively. Mean IC(50) of vardenafil against phosphodiesterase-5A1 to A3 was 0.41 +/- 0.15, 0.23 +/- 0.08 and 0.45 +/- 0.06 nM, respectively. CONCLUSIONS: Phosphodiesterase-5A1 and A2 had similar K(m) values, while phosphodiesterase-5A3 had a much higher K(m) and, thus, lower cyclic guanyl monophosphate catalytic activity. Phosphodiesterase-5A2 and A3 had similar K(d) values, while phosphodiesterase-5A1 had higher K(d) and, thus, lower cyclic guanyl monophosphate binding activity. Vardenafil was more potent (3 to 12-fold) than sildenafil for inhibiting the catalytic activity of all 3 human phosphodiesterase-5 isoforms with phosphodiesterase-5A2 showing the highest differentiation (12-fold).