Encyclopedia of Psychopharmacology

Living Edition
| Editors: Ian P. Stolerman, Lawrence H. Price

Phosphodiesterase Inhibitors

  • Jos PrickaertsEmail author
Living reference work entry
DOI: https://doi.org/10.1007/978-3-642-27772-6_403-2
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Synonyms

PDE inhibitors

Definition

There are 11 families of phosphodiesterases (PDEs; PDE1–PDE11), which degrade the second messengers cAMP and/or cGMP. The activity of PDEs can be selectively inhibited with drugs. The most widely known PDE inhibitor is sildenafil, which is one of the three PDE5 inhibitors approved for the treatment of erectile dysfunction and also arterial pulmonary hypertension. In addition, two PDE3 inhibitors are approved for treating congestive heart failure or intermittent claudication, respectively. Recently, one PDE4 inhibitor has been approved for the treatment of chronic obstructive pulmonary disease. At the moment, PDE inhibitors are explored as possible therapeutic CNS drug targets for memory loss (PDE1, PDE2, PDE4, PDE5, PDE9), Alzheimer’s disease (PDE3, PDE4, PDE5, PDE7, PDE9), Parkinson’s disease (PDE1, PDE4, PDE7), Huntington’s disease (PDE1, PDE4, PDE5, PDE10), anxiety (PDE2, PDE5), depression (PDE4), schizophrenia (PDE3, PDE10), pain (PDE4, PDE5), or stroke (PDE3, PDE5).

Pharmacological Properties

History

In 1886, the activity of PDEs was actually first described as it was noted that caffeine had bronchodilator properties. Later on, this effect was attributed to cyclic nucleotide cAMP and to caffeine-inhibited cAMP-specific PDEs. In 1970, PDEs were identified in rat and bovine tissue, and it was demonstrated that PDEs hydrolyze the phosphodiesteric bond of cAMP and cGMP (Bender and Beavo 2006). From then on, more PDEs were identified and characterized. Until now, 21 classes of genes for PDEs in humans, rats, and mice have been identified.

PDEs have been classified into 11 families (PDE1–PDE11) based on several criteria such as subcellular distributions, mechanisms of regulation, and enzymatic and kinetic properties. Most of these families have more than one gene product (e.g., PDE4A, PDE4B, PDE4C, PDE4D). In addition, each gene product may have multiple splice isoform variants (e.g., PDE4D1–PDE4D9). In total, there are more than 100 specific PDEs (Bender and Beavo 2006).

Caffeine is a nonselective PDE inhibitor, and it also inhibits cGMP-specific PDEs such as PDE5. cGMP causes vasodilatation in blood vessels by regulating their smooth muscle physiology. In addition, PDE5 also has an action on smooth muscles of contractile organs such as the penis. The most widely known PDE5 inhibitor is sildenafil. It was initially developed for the treatment of arterial hypertension and angina pectoris (Puzzo et al. 2008). In 1998, sildenafil was approved by the US Food and Drug Administration (FDA) for the treatment of erectile dysfunction and marketed under the name Viagra. Under the name of Revatio, it was also approved for the therapy of pulmonary artery hypertension in 2005.

The discovery of sildenafil started the research and development of numerous inhibitors of PDE5. At the same time, it stimulated researchers to explore other classes of PDEs for their therapeutic potential in different disorders. In addition, the previously explored PDEs, such as PDE4, were reevaluated after first being dismissed as a fruitful target due to side effects and a lack of specificity or efficacy of the developed PDE inhibitors (Esposito et al. 2009). For instance, in 1984, the PDE4 inhibitor rolipram was developed as a putative antidepressant, but it never made it to the market due to severe emetic side effects (e.g., nausea, vomiting).

Mechanisms of Action

PDEs hydrolyze the second messengers cAMP and/or cGMP, which are synthesized by adenylate and guanylate cyclase, respectively. However, the intracellular concentrations of both cyclic nucleotides are especially regulated by the PDE activity as its hydrolysis capacity far exceeds the capacity for synthesis. Besides this absolute and temporal regulation of cyclic nucleotides, PDEs contribute to their compartmentalized signaling as different PDEs are localized at some specific sites in the cell such as the plasma or nuclear membrane or cytosol. Thus, PDEs play a key role in the intracellular, signal transduction pathways in various biological systems as is illustrated in Fig. 1. cAMP and cGMP transfer an extracellular signal (e.g., neurotransmitter or hormone) to their effector proteins, protein kinase A and protein kinase G, respectively. Both kinases phosphorylate other enzymes or transcription factors, thus influencing the signal transduction. In addition, both cyclic nucleotides regulate their corresponding cyclic nucleotide-gated ion channels, which depolarize synaptic terminals and thus influence signaling pathways. For instance, cGMP regulates cGMP-gated ion channels and thus directly regulates the ion flux, which depolarizes the presynaptic terminal and influences glutamate release. Eventually, changes in signal transduction are translated into a biological system-dependent physiological and cellular response (Keravis and Lugnier 2012; Menniti et al. 2006; Puzzo et al. 2008; Reneerkens et al. 2009).
Fig. 1

Intracellular signal transduction pathways. An extracellular signal (e.g., neurotransmitter or hormone) activates adenylate cyclase (AC) and guanylate cyclase (GC), which produce their corresponding cyclic nucleotides out of ATP and GTP, respectively. cAMP activates protein kinase A (PKA), and cGMP activates protein kinase G (PKG). Both PKA and PKG can phosphorylate other enzymes or transcription factors such as CREB in the nucleus. Besides gene expression, cAMP and cGMP also regulate cAMP- and cGMP-gated ion channels, respectively, which depolarize the synaptic terminals. Eventually, these processes will result in a cellular response. Phosphodiesterases (PDEs) hydrolyze cAMP and/or cGMP leading to the formation of the inactive 5′-cAMP and 5′-cGMP, respectively. PDE inhibitors are selective for cAMP- and/or cGMP-degrading PDEs. In this way, a selective PDE inhibitor can specifically influence the cellular response of a biological system (Adapted from Puzzo et al. 2008)

PDEs itself are regulated by intracellular cyclic nucleotide concentrations, phosphorylation (e.g., protein kinase G), interaction with regulatory proteins, subcellular compartmentalization, and binding of Ca2+/calmodulin (Cheng and Grande 2007).

The specific localization of the different PDEs in the brain and the body will determine which particular physiological function may be influenced by some PDE inhibitors, but not by others. Table 1 gives an overview of the distribution of the different PDEs (for a detailed overview of the different PDE splice isoforms mRNA distribution in the brain and body of humans, see Lakics et al. 2010). Obviously, the PDE5 inhibitor sildenafil can be used for the treatment of erectile dysfunction since PDE5 is expressed in human cavernosal smooth muscle. Since PDE10A is highly expressed in the striatum where it regulates signal transduction in the cortico–striato–thalamic circuit, it is an interesting target for schizophrenia and related disorders of basal ganglia function. In contrast, PDE4 is highly expressed in the hippocampus, which is a key structure in the limbic system and is, therefore, considered as a useful target for treatment of mood disorders or cognitive deficits.
Table 1

Localization of different phosphodiesterases (PDEs) in the body and brain of rodents and humans in adulthood

PDE

Localization in body

Localization in the brain

PDE1A–C

Heart, smooth muscles, lungs, pancreas, kidneys, bladder, testes

Hippocampus, cortex, olfactory bulb, striatum (highest expression levels), thalamus, amygdala, cerebellum; expression levels are in general highest for 1A and lowest for 1C

PDE2A

Heart, liver, spleen, pancreas, adrenals, skeletal muscles, bladder, platelets

Hippocampus, cortex, striatum, hypothalamus, amygdala, midbrain

PDE3

Heart, smooth muscles, lungs, liver, pancreas, kidneys, platelets

Throughout the brain low expression levels

PDE4A–D

Wide variety of tissues: e.g., smooth muscles, skeletal muscles, lungs, liver, spleen, pancreas, kidneys, bladder, testes

Hippocampus, cortex, olfactory bulb, striatum, thalamus, hypothalamus, amygdala, midbrain, cerebellum; expression levels are in general highest for 4B and lowest for 4C

PDE5A

Smooth muscles, skeletal muscles, lungs, pancreas, kidneys, bladder, platelets

Hippocampus, cortex, cerebellum

PDE6

Rod and cone cells in retina

Pineal gland

PDE7A–B

Heart, skeletal muscles, liver, pancreas, kidneys, testes

Hippocampus, cortex, olfactory bulb, striatum, thalamus, hypothalamus, midbrain; expression levels are in general highest for 7B

PDE8A–B

Heart, liver, pancreas, kidneys, adrenals, lungs, testes, thyroid

Hippocampus, cortex, olfactory bulb, striatum, thalamus, hypothalamus, midbrain; expression levels are in general highest for 8B

PDE9A

Lungs, spleen, pancreas, kidneys, bladder, prostate, various gastrointestinal tissues

Hippocampus, cortex, olfactory bulb, striatum, thalamus, hypothalamus, amygdala, midbrain, cerebellum

PDE10A

Heart, skeletal muscles, lungs, liver, pancreas, kidneys, testes, thyroid

Hippocampus, cortex, striatum (highest expression levels), midbrain, cerebellum

PDE11A

Skeletal muscles, liver, pancreas, kidneys, testes, prostate, thyroid

Throughout the brain low expression levels

Only clear expression levels are taken into consideration. Note that this table does not provide information with respect to the level of expression (protein or mRNA) of the different PDEs

Pharmacokinetics

Only the pharmacokinetics of compounds that have been approved by the FDA and are also being evaluated for CNS applications is described.

The PDE3 inhibitor cilostazol is given orally and has a half-life of about 11–13 h. Cilostazol is metabolized and eliminated by CYP3A4 and CYP2C19, two isoenzymes of the cytochrome P450 system in the liver, after which it is predominantly excreted via the kidneys into the urine (Chapman and Goa 2003).

The PDE4 inhibitor roflumilast is metabolized in the liver by CYP3A4 and CYP1A2 to the main metabolite roflumilast N-oxide, with CYP3A4 being the major contributor. Roflumilast N-oxide is also active as PDE4 inhibitor. After oral dosing, the half-life of roflumilast and roflumilast N-oxide are about 17 and 30 h, respectively. Roflumilast is also metabolized to a minor extent to a pharmacologically inactive metabolite by CYP3A4 and CYP1A2, with a minor contribution from CYP2C19. Roflumilast N-oxide is metabolized and eliminated by CYP3A4. The inactive metabolites are predominantly excreted via the urine and to a lesser extent via the feces (Lahu et al. 2011).

The PDE5 inhibitors sildenafil, vardenafil, and tadalafil are given orally and are rapidly absorbed in the gastrointestinal tract at the level of the small intestine. The half-life of sildenafil and vardenafil is about 3–4 h. In contrast, tadalafil has a long half-life of about 18 h. All three compounds are metabolized and eliminated in the liver by CYP3A4. For sildenafil, CYP2C9 is also partly involved. All three metabolized PDE5 inhibitors are excreted predominantly via the liver into the feces but also via the kidneys into the urine (Puzzo et al. 2008).

If a compound can be used to target CNS-related disorders, it is vital that it crosses the blood–brain barrier (BBB). Especially when the compound itself is required centrally to be effective, as otherwise alternatives have to be developed such as a central administration application for the drug. The abovementioned PDE inhibitors, which are approved by the FDA for non-CNS indications but which are currently being evaluated for CNS application, were initially considered to have insignificant brain penetration or brain penetration only dependent on BBB permeability occurring in pathological conditions such as ischemia (e.g., tadalafil). However, there is accumulating preclinical and clinical data showing that cilostazol, sildenafil, vardenafil, tadalafil, and roflumilast can enter the brain significantly to be biologically active.

Efficacy

Table 2 summarizes the PDE inhibitors currently on the market or in development. For CNS applications, also preclinical evidence is mentioned. More detailed information about the status of clinical development of a particular compound can be found at http://clinicaltrials.gov/. To check whether a drug is approved by the FDA, see http://www.accessdata.fda.gov/scripts/cder/drugsatfda/.
Table 2

Overview of the PDEs and their possible clinical applications

Type

Number of genes

Property

Substrate

Selective inhibitors

FDA-approved and possible therapeutic applications. CNS applications in bold

PDE1

3

Ca2+-CaM stimulated

cAMP/cGMP

Vinpocetine, calmidazolium

Memory improvement – vinpocetine (Cavinton, Intelectol, Cognitex)

Cognitive impairment in Alzheimer’s disease – vinpocetine (failed)

Parkinson’s disease – vinpocetine (preclinical)

Huntington’s disease – vinpocetine (preclinical)

PDE2

1

cGMP stimulated

cAMP/cGMP

BAY 60-7550, ND7001, EHNA, exisulind

Memory improvement/Alzheimer’s disease – Bay 60-7550 (preclinical)

Anxiety – BAY 60-7550, ND7001 (preclinical)

Cancer – exisulind (Aptosyn)

PDE3

2

cGMP inhibited

cAMP

Cilostazol, cilostamide, enoximone, milrinone, lixazinone, OPC-33540, SK&F 95654

Stroke – cilostazol

Cognitive impairment in mild to moderate Alzheimer’s disease – cilostazol (cotreatment with acetylcholinesterase inhibitor donepezil)

Schizophreniacilostazol

Intermittent claudication – cilostazol (Pletal)

Congestive heart failure – milrinone (Primacor)

Congestive heart failure – enoximone (Perfan)

PDE4

4

cAMP specific

cAMP

Rolipram, Ro 20-1724, cilomilast, roflumilast, ibudilast, MK0952, V11294A, L-826,141, AWD 12-281, HT0712, SCH 351591

Cognitive impairment in mild to moderate Alzheimer’s disease – MK0952

Parkinson’s disease – rolipram (preclinical)

Huntington’s disease – rolipram (preclinical)

Depression – rolipram

Pain – ibudilast

Asthma, chronic obstructive pulmonary disease (COPD) – cilomilast (Ariflo), roflumilast

PDE5

1

cGMP specific

cGMP

Sildenafil, vardenafil, tadalafil, SK&F 96231, DMPPO, udenafil, avanafil, DA-8159

Memory improvement/Alzheimer’s disease – sildenafil, vardenafil, tadalafil (preclinical)

Memory improvement – sildenafil (failed), vardenafil (failed), udenafil

Huntington’s disease – sildenafil, vardenafil (preclinical)

Anxiety – sildenafil, tadalafil (preclinical)

Pain – sildenafil (preclinical)

Erectile dysfunction – sildenafil (Viagra), vardenafil (Levitra), tadalafil (Cialis)

Female sexual arousal disorder (FSAD) – sildenafil

Pulmonary hypertension – sildenafil (Revatio), tadalafil (Adcirca)

PDE6

4

Photoreceptor

cGMP

Sildenafil, vardenafil, tadalafil, DMPPO

PDE7

2

cAMP high affinity

cAMP

BRL 50481, IC242, BMS-586353, S14

Alzheimer’s disease – S14 (preclinical)

Parkinson’s disease – S14, BRL 50481 (preclinical)

PDE8

2

cAMP high affinity

cAMP

PF-04957325

PDE9

1

cGMP high affinity

cGMP

BAY 73-6691, PF-04447947

Cognitive impairment in mild to moderate Alzheimer’s disease – PF-04447947 (failed)

PDE10

1

cAMP inhibited

cGMP

Papaverine, PF-02545920, PQ-10, TP-10

Schizophrenia – PF-02545920 (failed)

Huntington’s disease – TP-10 (preclinical)

PDE11

1

Dual substrate

cAMP/cGMP

Tadalafil

The properties and substrate specificity are depicted. In addition, the commonly used selective and nonselective PDE inhibitors are mentioned. FDA-approved compounds as well as compounds in clinical phases of development are given. For possible CNS applications, also preclinical evidence is given. All CNS applications are in bold

Nonselective inhibitors are the following: caffeine, theophylline, 3-isobutyl-1-methylxanthine (IBMX; all but PDE8), dipyridamole (PDE5, PDE6, PDE7, PDE9, PDE10, PDE11), zaprinast (PDE5, PDE6, PDE9, PDE10, PDE11), SCH 51866 (PDE1, PDE5, PDE7, PDE9, PDE10, PDE11), and E4021 (PDE5, PDE6, PDE10, PDE11)

The PDE1 inhibitor vinpocetine (Cavinton, Intelectol, Cognitex) is not approved by FDA as a drug, but it is widely used as a supplement for vasodilation and as a nootropic for the improvement of memory. The latter effect is likely to be related to vasodilatation. However, the relevance of the possible therapeutic effect of vinpocetine can be questioned, and it has not been shown to be of real benefit in the treatment of Alzheimer’s disease patients (Szatmari and Whitehouse 2003). Preclinically, vinpocetine has been reported to improve motor function and biochemical abnormalities in rat models of Parkinson’s disease and Huntington’s disease, respectively (Sharma et al. 2013). This suggests potential of PDE1 inhibition for the treatment of these movement disorders.

The first selective PDE2 inhibitor available was BAY 60-7550, and it has been shown to improve memory in rodents and a mouse model of Alzheimer’s disease (e.g., Reneerkens et al. 2009; Sierksma et al. 2013). Recently, BAY 60-7550 and the PDE2 inhibitor ND7001 are being preclinically evaluated as possible anxiolytics (Keravis and Lugnier 2012; Xu et al. 2011). Exisulind (Aptosyn) is another developed PDE2 inhibitor, which also has the PDE5-inhibiting activity. This drug induces apoptosis in a broad range of cancer cell lines and inhibits the formation and growth of cancer in several animal models. Presently, this compound has been tested in clinical Phase-III trials for breast, lung, prostate, and colon tumors.

Cilostazol (Pletal) is a PDE3 inhibitor and has been approved by the FDA for the treatment of intermittent claudication. It is also being investigated in a Phase-IV study as a prevention of stroke recurrence and safety for bleeding complications in acute stroke. Furthermore, cilostazol has been investigated in three clinical studies to examine the effects on cognition in mild to moderate Alzheimer’s disease patients who were already on a neuroprotective treatment, mostly with the acetylcholinesterase inhibitor donepezil. However, the conflicting results of those studies do not allow drawing a clear conclusion on possible cognition-enhancing effects yet. Cilostazol has also been tested on cognitive function in schizophrenic patients on antipsychotic treatment. However, results were not uniform enough to be conclusive.

Enoximone (Perfan) and milrinone (Primacor) are also PDE3 inhibitors, which have been developed for the treatment of congestive heart failure. Milrinone has been approved by the FDA for this indication, while enoximone has been tested up to Phase III of development. Their mode of action is via cAMP/PKA-mediated facilitation of intracellular Ca2+ mobilization. In addition, vasodilatory action plays a role in improving hemodynamic parameters in certain patients.

PDE4 inhibitors were initially considered as a possible target for the development of drugs for the treatment of depressive disorders (Esposito et al. 2009). In this respect, the PDE4 inhibitor rolipram has been widely investigated. First clinical studies showed a good antidepressant response to rolipram treatment. However, rolipram produces severe dose-limiting emetic side effects including headache, gastric hypersecretion, nausea, and vomiting in humans. This has put a serious hold on the further development of rolipram and other related PDE inhibitors. It also prevented rolipram from reaching the market. But since the approval of PDE5 inhibitors for the treatment of erectile dysfunction, PDE inhibitors in general have received renewed interest as a possible therapeutic target for the treatment of diseases. Along similar lines, a clinical Phase-II trial is ongoing to reevaluate the antidepressant properties of rolipram. Preclinically, rolipram has been tested in rodent models of Parkinson’s disease and Huntington’s disease, respectively, and was found to exert neuroprotective effects in the striatum, suggesting a beneficial role of PDE4 inhibitors in the treatment of these movement disorders (Sharma et al. 2013). However, this needs to be tested clinically.

At the moment, “second-generation” PDE4 inhibitors are being developed, which are supposed to have less-emetic side effects, and are being studied for a variety of disorders. A clinical Phase-II trial has been completed investigating whether the PDE4 inhibitor MK0952 improves cognition in patients with mild to moderate Alzheimer’s disease. However, its results have never been disclosed. Additionally, the PDE4 inhibitor HT-0712 was tested on age-related memory impairment and reported to improve long-term memory. However, this has never been followed up. Furthermore, the PDE4 inhibitors cilomilast (Ariflo) and roflumilast (Daxas, Daliresp) have been clinically tested up to Phase III as anti-inflammatory drugs for the treatment of asthma and chronic obstructive pulmonary disease (COPD). Cilomilast has not been approved by the FDA, while in 2011, roflumilast was approved as an inflammatory drug for the treatment of COPD. Recently, a Phase-II study has started to investigate whether roflumilast improves memory in healthy human volunteers. Finally, ibudilast (or AV-411) is another PDE4 inhibitor in development as an anti-inflammatory drug. However, this compound is not only inhibiting PDE4 but it also suppresses drug or virus-induced inflammatory activity of glial cells, and for this reason, other clinical CNS applications are being explored in Phase-II studies, i.e., pain and drug abuse.

The PDE5 inhibitor sildenafil was the first FDA-approved treatment of erectile dysfunction. Although PDE5 inhibition causes relaxation of smooth muscles in blood vessels, it is also of particular importance for the treatment of erectile dysfunction in that it causes relaxation of smooth muscles in organs such as the penis (Puzzo et al. 2008). In women, sildenafil has an effect on the contractile state of the uterus and blood flow in the clitoris. Therefore, sildenafil has also been considered as a possible treatment for female sexual arousal disorder (FSAD) (completed Phase-II trial). Sildenafil is on the market as Viagra. Two more PDE5 inhibitors also reached the market for the treatment of erectile dysfunction as well, vardenafil (Levitra) and tadalafil (Cialis), respectively. Vardenafil is the more-potent PDE5 inhibitor when compared with sildenafil and tadalafil. The latter is considered as second-generation oral drug, and it has the longest half-life, while its effects last the longest as well.

Because of its vasodilatatory properties, sildenafil and tadalafil are also FDA approved under the names of Revatio and Adcirca, respectively, for the treatment of hypertension of the pulmonary artery. For the same application, a Phase-III trial of vardenafil was recently completed.

Sildenafil has been successfully used to treat serotonin reuptake inhibitor (SSRI) associated erectile dysfunction. In women, a Phase-IV study has been completed and was reported to show efficacy of sildenafil in women with SSRI-associated sexual dysfunction. Whether sildenafil treatment also improves mood and/or quality of life in women and men who are treated for antidepressant-induced sexual dysfunction needs further study. In this respect, a Phase-IV study has been completed that measured the impact of treatment with sildenafil on the depressive symptoms and quality of life in male patients with erectile dysfunction who have untreated depressive symptoms. However, its results have not been disclosed. Yet it will be difficult to disentangle whether a possible beneficial effect on mood is due to treatment of the sexual dysfunction or whether PDE5 inhibition directly leads to an improvement in depressive symptoms and thus an attenuation of the erectile/sexual dysfunction. Of note, no direct antidepressant potential of sildenafil has been found in preclinical rodent students (e.g., Brink et al. 2008). PDE5 inhibition is also preclinically being evaluated as a possible anxiolytic, but an anxiolytic effect appears apparent only after chronic treatment with sildenafil, whereas acute treatment is even anxiogenic (Liebenberg et al. 2012).

A Phase-I study was evaluating whether sildenafil has neuroprotective properties in the treatment for stroke. However, in 2011, this study was terminated because of the failure to recruit in the expected period. Another interesting CNS application could be neuropathic pain as sildenafil was effective in the treatment of pain in animal models (e.g., Ambriz-Tututi et al. 2005). This still awaits confirmation in clinical studies. This also holds for Huntington’s disease as sildenafil as well as vardenafil had neuroprotective effects in the striatum as observed in a rat model of Huntington’s disease (Sharma et al. 2013).

There is some evidence that PDE5 inhibition has cognition-enhancing and neuroprotective effects in several animal species including mouse models of Alzheimer’s disease (e.g., Reneerkens et al. 2009; García-Barroso et al. 2013). However, until now, convincing evidence in humans is still lacking. Three studies have explored the effects of sildenafil or vardenafil on human cognition in healthy human volunteers, but no clear effects on cognition were found. Sildenafil was also tested on cognitive function in patients with schizophrenia who were on antipsychotic treatment. However, sildenafil was not effective. In another study, the PDE5 inhibitor udenafil was tested in patients suffering from erectile dysfunction (Shim et al. 2011). Repeated dosing of udenafil was reported to improve cognitive (executive) function. Apparently, chronic treatment and/or selection of the best target patient population needs to be considered when testing a PDE5 inhibitor.

Recently, it has been found that the PDE7 inhibitor S14 reduced cognitive impairment as well as central plaques load and tau phosphorylation in a mouse model of Alzheimer’s disease (Perez-Gonzalez et al. 2013). This suggests that PDE7 inhibition might have therapeutic potential for the treatment of memory dysfunction and/or Alzheimer’s disease. In addition, PDE7 inhibition might also be a target for neuroprotection in Parkinson’s disease as S14, and the PDE7 inhibitor BRL 50481 prevented dopaminergic neuronal loss in a rat model of Parkinson’s disease (Sharma et al. 2013).

The first selective PDE9 inhibitor available was BAY 73-6691, and it improved memory performance in rodents (e.g., Reneerkens et al. 2009). This was also found for the PDE9 inhibitor PF-04447943, which was also tested in a Phase-II study with mild to moderate Alzheimer’s disease patients. However, no effect was found on cognition. It was suggested that the treatment duration may not have been long enough and/or a less cognitively impaired target population, e.g., age-associated cognitive impaired subjects, could have been a better choice for treatment.

Until very recently, the PDE10A inhibitor PF-02545920 (or MP-10) was in a second Phase-II clinical study for the treatment of schizophrenia after the first study had been terminated for reasons unknown. However, the outcome of the second study showed that chronic PF-02545920 treatment had no effect on positive and negative symptoms in schizophrenia patients. In addition, adverse events including akathisia (inner restlessness, inability to remain motionless) and dystonia (muscle contractions causing twisting and repetitive movements or abnormal postures) were observed. Of note, the action mechanism of PDE10A inhibition was attributed to be modulation/normalization of dopaminergic cortico–striato–thalamic function. In this respect, increased cAMP levels are assumed to be of more importance than cGMP, although PDE10A itself predominantly hydrolyses cGMP. Interestingly, PDE10 inhibition might still be beneficial in treating Huntington’s disease as the PDE10 inhibitor TP-10 has been demonstrated to be neuroprotective in rodent models of Huntington’s disease (Sharma et al. 2013).

Safety/Tolerability

Only safety and tolerability of compounds which have been approved by the FDA and are also being evaluated for CNS applications are discussed.

Possible side effects of the PDE3 inhibitor cilostazol include most commonly headache, diarrhea, abnormal stools, and since it is a quinolinone derivative also irregular heart rate and palpitations. Therefore, it is dangerous for people with severe heart failure and can only be given to people without this indication.

The most commonly reported side effects of roflumilast include diarrhea, weight loss, nausea, abdominal pain, and headache. Three suicides have been observed in a COPD patient pool versus none in the placebo pool. This was identified as a significant concern by the FDA, although none of the suicides was identified as being related to the study medication. There are no indications for cardiovascular effects associated with roflumilast use.

Sildenafil, vardenafil, as well as tadalafil have side effects such as headaches, facial flushing, nasal congestion, and dyspepsia (indigestion). However, these effects are transient. All three PDE inhibitors can act on PDE6, which is present in the retina; and high doses have been reported to cause adverse visual events, including non-arteritic anterior ischemic optic neuropathy and, thus, can cause vision problems (e.g., blurred vision). Moreover, tadalafil also potently inhibits PDE11, an enzyme with an unknown physiological function. Because of the possible vasodilatatory effects, these compounds are not suited for patients with cardiovascular indications or hypotensives.

An approach to circumvent the side effects of PDE inhibitors is to develop very selective inhibitors at the level of the splice isoform variant. At the same time, the function of interest may be more specifically targeted. For example, there are three splice isoform variants of PDE5, PDE5A1–PDE5A3 (Puzzo et al. 2008). While the first two are found nearly in all tissues, the third one is specific to smooth muscles.

The emetic side effects of the available PDE4 inhibitors, which inhibit more or less all four isoforms PDE4A, PDE4B, PDE4C, and PDE4D, prevented until now that they have reached the market (Esposito et al. 2009). Preclinical animal research already indicated that the antidepressant potential of PDE4A in the hippocampus was related to specific splice variants of PDE4A (Xu et al. 2011). Moreover, in a patient with Alzheimer’s disease, it was found that the expression of most splice isoform variants of PDE4D was decreased in the hippocampus, whereas two variants were increased. These findings underscore the need to develop specific inhibitors of PDE4 splice variants as cognition enhancers or antidepressants without unwanted side effects (Reneerkens et al. 2009). An example of this is the recent development of selective inhibitors for PDE4D which are devoid of emetic effects or have at least greatly reduced emetic effects (Gurney et al. 2011).

Conclusions

Besides the already approved clinical application of erectile dysfunction, pulmonary hypertension, congestive heart failure, intermittent claudication, and chronic obstructive pulmonary disease, PDE inhibitors offer a promising drug target for a wide array of diseases including CNS-related disorders such as Alzheimer’s disease, depression, schizophrenia, or stroke. Yet, the future in disease-specific PDE inhibitors lies in the development of splice isoform variant-specific inhibitors that have limited aversive side-effect profiles within the effective dose range for its clinical application.

Cross-References

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  1. 1.Department of Psychiatry and NeuropsychologyUniversity of MaastrichtMaastrichtThe Netherlands