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Potency, selectivity, and consequences of nonselectivity of PDE inhibition



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: tadalafil>vardenafil>sildenafil) may result in vasodilation and tachycardia. Inhibition of PDE6 (selectivity: tadalafil>vardenafilsildenafil), 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.


The 11 known phosphodiesterase (PDE) families comprise at least 60 distinct PDE species. They differ in their substrate specificity, their kinetic properties, and in their tissue distribution (Table 1). PDE enzymes participate in the regulation of all cellular functions, depending on the cyclic nucleotides that serve as second messengers. PDE enzymes hydrolyze the phosphodiester bond of cyclic adenosine monophosphate (cAMP) and of cyclic guanosine monophosphate (cGMP). Therefore, a PDE inhibitor can elevate the intracellular concentration of cAMP or cGMP depending on the particular substrate specificity of the respective PDE.

Table 1 Substrate specificities and distributions of PDE families

PDE5 is the predominant cGMP metabolizing PDE in cavernosal tissue and in penile arteries, but it is also localized in all vascular smooth muscle cells (SMCs) as well as in platelets and other tissues, such as the lung. Among the three pharmacologically and biochemically characterized PDE5 inhibitors—sildenafil, vardenafil, and tadalafil—sildenafil and vardenafil are typical substrate analogues as their structures mimic that of cGMP, which is the natural substrate of PDE5. Both sildenafil and vardenafil bind at the catalytic active center of PDE5, but because they are not hydrolyzed, sildenafil and vardenafil can inhibit the catalytic activity of the enzyme in a competitive manner.

The structures of sildenafil and vardenafil differ in particular by the molecular configuration of their nitrogen atoms in the heterocyclic ring system (Figure 1). The structure of tadalafil departs entirely from that of both sildenafil and vardenafil.1,2,3 Biochemically, PDE5 inhibitors can be characterized by their potency and by their selectivity with respect to other PDEs. Both potency and selectivity influence the pharmacodynamics, and the clinical properties of a PDE5 inhibitor.

Figure 1

Chemical structures of vardenafil, sildenafil, and tadalafil. Source: Haning H et al. Imidazo[5,1-f]triazin-4(3H)-ones, a new class of potent PDE 5 inhibitors. Bioorg Med Chem Lett 2002; 12(6): 865–868.

Potency is commonly expressed as IC50, or the drug concentration required to reduce the activity of the tested PDE by 50%. The lower the value of the IC50, the higher the potency of the inhibitory agent. The reported values of IC50 can vary considerably depending on the enzyme preparation employed and assay conditions (eg, the substrate concentration). Consequently, only data obtained under identical analytical conditions can be compared. Sildenafil, vardenafil, and tadalafil are all potent PDE5-inhibitors and vardenafil displays the highest potency. It inhibits PDE5 at concentrations 10-fold lower than does sildenafil and 13-fold lower than tadalafil. Its IC50 is 0.7 versus 6.6 nM for sildenafil and 9.4 nM for tadalafil.1 The scientific literature reports significantly different IC50 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. Selectivity is defined as the ratio between the IC50 for a given PDE and the IC50 for PDE5. The greater that ratio is, the more selective the inhibitor for PDE5 compared to the comparative PDE. With some exceptions, all three PDE5 inhibitor compounds are selective. Table 2 summarizes the selectivity ratios of vardenafil and sildenafil.1

Table 2 Selectivity of PDE inhibitors based on human recombinant PDE preparations

With respect to PDE6, the selectivity ratio of vardenafil is 15, compared to sildenafil with a selectivity ratio of approximately 7. This means that 15-fold higher concentrations of vardenafil and seven-fold higher concentrations of sildenafil are necessary to inhibit PDE6 in comparison to PDE5. With a selectivity ratio of 780 for PDE6, tadalafil is clearly more selective than either vardenafil or sildenafil.2,4

With respect to PDE1, selectivity of vardenafil is approximately 140, and about 350 with respect to PDE11. For both PDE1 and PDE11, sildenafil shares similar selectivity ratios with vardenafil at 40 and 200, respectively. Selectivity ratios with respect to other PDEs exceed 1000.1 Although extremely selective with respect to PDE1, tadalafil potently inhibits PDE11 (IC50=37 nM), and therefore its selectivity ratio with respect to this PDE is only 5.6

Selectivity ratios also vary significantly between different scientific reports because they are calculated from IC50 values. However, for sildenafil, vardenafil, and tadalafil, the rank order of selectivity remains the same.

  • For PDE1, the order of selectivity is: tadalafil>vardenafil>sildenafil.

  • For PDE6, the order of selectivity is: tadalafil>vardenafilsildenafil.

  • For PDE11, the order of selectivity is: sildenafil>vardenafil>tadalafil.

What could be the clinical relevance of the observed selectivity profiles of these three compounds? With respect to PDE1, selectivity may be clinically significant for several reasons. PDE1 is expressed in the brain, in myocardial cells, and in vascular SMCs. The three subtypes of PDE1—PDE1A, PDE1B, and PDE1C—are all Ca2+-calmodulin activated. PDE1A and PDE1B affect cGMP to a greater degree than cAMP. PDE1C exerts an equivalent effect on cGMP and cAMP, the Vmax for cAMP and cGMP being similar. Nonselectivity of PDE5 inhibitors with respect to all PDE1 subtypes may induce vasodilatation, flushing, and tachycardia. PDE1C may play a significant role in the proliferation of SMC, because this subtype is highly expressed in proliferating SMCs. To the contrary, nonproliferating cells exhibit only low levels of PDE1C expression. It can be speculated that inhibition of PDE1C could produce beneficial effects due to its putative inhibition of SMC proliferation, an event that contributes importantly to the pathophysiology of atherosclerosis.

PDE6 is only expressed in the retina and plays a decisive role in signal transduction of vision. Inhibition of this enzyme can induce visual disturbances, which have occurred at the highest clinically applied dose of sildenafil and to a lesser extent with vardenafil. No visual disturbances have been reported with tadalafil use.

The physiological relevance of PDE11 has not yet been established. PDE11 is expressed in the liver, kidney, pituitary gland, in skeletal muscle, myocardium, prostate, corpus cavernosum, and to a high degree in the testes.

Musculoskeletal pain, in particular back pain, has been reported during therapy for erectile dysfunction (ED) with PDE5 inhibitors. The effects are more significant with tadalafil than with sildenafil or vardenafil. It has been speculated that back pain may be attributed to tadalafil inhibition of PDE11 or to tadalafil's comparatively longer half-life. However, to date, scant evidence exists to support these hypotheses.2

The clinical relevance of selectivity-related issues depends in large part on the maximal plasma concentration of the respective compounds. In therapeutic doses, the plasma concentrations of sildenafil and vardenafil may reach the IC50 of PDE6, a level not expected for tadalafil. Clearly, tadalafil will inhibit PDE11 (Table 1). None of the three compounds is believed to inhibit other PDE families at therapeutic or supratherapeutic concentrations.

Indirectly, PDE5 inhibition may affect the pharmacodynamics of PDE3. PDE3 is abundant in many tissues, including the myocardium, vascular smooth muscle, platelets, hepatocytes, adipose tissue, penile tissue and the pancreas. There is evidence to suggest that PDE3 and PDE5 are the main PDE isoforms involved in pulmonary artery relaxation.8 The Vmax of PDE3 is 2–10-fold higher for cAMP compared with cGMP and is inhibited by physio-logically relevant concentrations of cGMP. If one cell type expresses both enzymes, the cGMP-inhibited PDE3 and the cGMP-specific PDE5, even a perfectly selective inhibition of PDE5 could precipitate the inhibition of PDE3 indirectly, due to increased cGMP levels induced by PDE5 inhibition.9 Therefore, if both PDE5 and PDE3 are expressed in myocardial cells or in the Purkinje fibers of the heart, an increase in heart rate and a positive inotropic effect could result as a consequence of PDE3-induced PDE5 inhibition. However, experimental evidence increasingly indicates that PDE5 is neither expressed in cardiomyocytes nor in Purkinje fibers.10,11 Indirectly induced vasodilation and inhibition of platelet aggregation due to the colocalization of PDE5 and PDE3 in these cells appears possible, but is lacking in clinical relevance. As PDE3 is localized in penile tissue, it cannot be excluded that elevated cAMP also contributes to the erectogenic effect of PDE5 inhibitors.

Based on 3 y of cardiovascular safety experience with sildenafil, important yet unanswered issues that should be addressed include:

  1. 1)

    Are there clinical implications to the intracellular incorporation of certain therapeutic compounds that might demonstrate high affinities for PDE receptor sites? Potential test sources include the rod outer segment of the retina and platelets. All therapeutically effective PDE inhibitors must be incorporated into the cell because all PDEs are localized in the cytoplasm and/or on intracellular membranes. Moreover, compounds that are targeted to the CNS or to PDE6 in the retina must cross the blood–brain barrier or the blood–retina barrier. Compounds that bind irreversibly and with high affinity to PDE enzymes are expected to be therapeutically difficult to manipulate. Experimental evidence exists to suggest that permanent inhibition of PDE6 in the retina could precipitate apoptosis of these cells. Other targets could include the inhibition of platelet function via PDE inhibition in order to achieve anti-aggregatory effects. In this case as well, irreversible inhibition could be dangerous. It has been speculated that permanent inhibition of PDE5 might be therapeutically useful not merely for a symptomatic but for a curative treatment of ED. However, clinical evidence has yet to be established.

  2. 2)

    Unlike tadalafil, vardenafil and sildenafil have not been shown to cross-react with PDE11. This suggests that the catalytic domain of PDE11 differs in an important way from that of PDE5. Is there potential for drug development that targets the unique substrate specificities of PDE5 and PDE11 with the objectives of:

    1. a)

      Identifying the physiologic function of PDE11 and

    2. b)

      Applying pharmacologic therapies to identifiable PDE11-related disorders?

Structurally, the most similar PDE enzymes are PDE5 and PDE6. Nevertheless, it is possible to synthesize PDE inhibitors that are both potent and selective for each of the known PDE families and for their subtypes as well, such as PDE1A, PDE1B, or PDE1C. However, it is not imperative that the existence of a selective and potent inhibitor either explains the physiologic function of the enzyme, or creates a new therapeutic principle. A detailed description and a variety of biological data derived from a PDE11 knockout mouse12 shows that although the function of the enzyme could be postulated from such an animal model, no clear physiological role of the enzyme could be deduced from the experimental findings. Clearly, a selective and potent PDE11 inhibitor might support currently available data. On the other hand, we have known for some years of selective and potent PDE2 inhibitors, but as yet have no evidence to elucidate the physiological role of the enzyme. Perhaps PDE function can only be detected under patho-physiological conditions. In that case, interpreting physiological function would require a respective pathophysiological model.


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Correspondence to E Bischoff.

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