Selectivity of sildenafil and other phosphodiesterase type 5 (PDE5) inhibitors against all human phosphodiesterase families

Gbekor, Eugene; Betheil, Sue; Fawcett, Lindsay; Mount, Natalie; Phillips, Stephen C.

doi:10.1016/s1569-9056(02)80240-8

Cited by 46 publications

(27 citation statements)

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“…We agree that a 40-fold selectivity of tadalafil for PDE5 over PDE11A4 does not completely exclude the possibility of crossreaction, but it reduces the likelihood of such an effect when compared with the five-fold tadalafil selectivity reported for the shortest isoform, PDE11A1. 4 We agree with Pomara et al that the potency of tadalafil for inhibiting the other three PDE11 variants (PDE11A1-11A3) needs to be evaluated, in a head-to-head manner with PDE11A4. However, we caution against drawing conclusions about the possible side-effects based solely on distribution of PDE11A mRNA transcripts.…”

supporting

confidence: 89%

Comment on: ‘Inhibition of phosphodiesterase 11 (PDE11) impacts on sperm quality’

Weeks

2005

Int J Impot Res

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supporting

confidence: 89%

Comment on: ‘Inhibition of phosphodiesterase 11 (PDE11) impacts on sperm quality’

Weeks

2005

Int J Impot Res

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“…The 40-fold selectivity ratio of tadalafil for PDE5 over PDE11 reported here is significantly higher than that reported previously using PDE11A1, instead of PDE11A4. 12 This discrepancy could be due to differences in the kinetic properties of PDE11A1 and PDE11A4 that may arise from differences in N-terminal regulatory domains between these variants.…”

Section: Biochemical Potency Of Cns and Cn Analogs For Inhibition Of mentioning

confidence: 99%

“…An initial study reported a relatively low selectivity (five-fold) of tadalafil for PDE5 over PDE11A1. 12 It has been suggested that PDE11 inhibition could account for the back pain and myalgia reported by some men taking tadalafil, as well as for alterations in spermatogenesis seen in dogs given tadalafil daily. [13][14][15] Interestingly, other PDE5 inhibitors have also been reported to cause similar side effects such as myalgia, 16 and a recent study concluded that there was no effect of tadalafil on spermatogenesis in men.…”

Section: Introductionmentioning

confidence: 99%

High biochemical selectivity of tadalafil, sildenafil and vardenafil for human phosphodiesterase 5A1 (PDE5) over PDE11A4 suggests the absence of PDE11A4 cross-reaction in patients

et al. 2004

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The physiological role of phosphodiesterase (PDE)11 is unknown and its biochemical characteristics are poorly understood. We have expressed human His-tagged PDE11A4 and purified the enzyme to apparent homogeneity. PDE11A4 displays K m values of 0.97 lM for cGMP and 2.4 lM for cAMP, and maximal velocities were 4-to 10-fold higher for cAMP than for cGMP. Given the homology between PDE11 and PDE5, we have compared the biochemical potencies of tadalafil (Cialist, Lilly-ICOS), vardenafil (Levitrat, Bayer-GSK), and sildenafil (Viagrat, Pfizer Inc.) for PDE11A4 and PDE5A1. PDE5A1/PDE11A4 selectivities are 40-, 9300-, and 1000-fold for tadalafil, vardenafil, and sildenafil, respectively. This suggests that none of these three compounds is likely to crossreact with PDE11A4 in patients.

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“…1 The scientific literature reports significantly different IC 50 values, but in all reports, vardenafil is identified as the most potent compound compared to sildenafil and tadalafil. [4][5][6][7] In addition to potency, high selectivity determines the clinical relevance and therapeutic efficacy of any PDE5 inhibitor. Selectivity means that only PDE5 should be inhibited and no other PDE.…”

Section: Introductionmentioning

confidence: 99%

Potency, selectivity, and consequences of nonselectivity of PDE inhibition

2004

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Phosphodiesterases (PDEs) play a decisive role in cyclic nucleotide-mediated intracellular signaling. As PDEs are expressed in a variety of tissues, selectivity is a prerequisite for a therapeutically applicable PDE inhibitor. Sildenafil, vardenafil, and tadalafil are selective for PDE5, with vardenafil exhibiting the highest potency and minimal inhibition of other PDEs, with the exception of PDE6. Tadalafil is extremely selective for PDE5, but also potently inhibits PDE11, an enzyme with unknown physiological function. As PDE1 is expressed in the brain, myocardium, and vascular smooth muscle cells, nonselectivity with respect to this enzyme (selectivity: tadalafil4 vardenafil4sildenafil) may result in vasodilation and tachycardia. Inhibition of PDE6 (selectivity: tadalafil4vardenafilDsildenafil), which is expressed only in retina and functions in visual transduction, can transiently disturb vision. PDE5 inhibitors may also indirectly inhibit PDE3 by increasing cyclic guanosine monophospate levels, thereby elevating heart rate and vasodilation while inhibiting platelet aggregation.

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Selectivity of sildenafil and other phosphodiesterase type 5 (PDE5) inhibitors against all human phosphodiesterase families

Cited by 46 publications

References 0 publications

Comment on: ‘Inhibition of phosphodiesterase 11 (PDE11) impacts on sperm quality’

Comment on: ‘Inhibition of phosphodiesterase 11 (PDE11) impacts on sperm quality’

High biochemical selectivity of tadalafil, sildenafil and vardenafil for human phosphodiesterase 5A1 (PDE5) over PDE11A4 suggests the absence of PDE11A4 cross-reaction in patients

Potency, selectivity, and consequences of nonselectivity of PDE inhibition

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