Selective Phosphodiesterase (PDE)-4 Inhibitors - Springer Link

Drugs R D 2006; 7 (2): 63-71 1174-5886/06/0002-0063/$39.95/0

REVIEW ARTICLE

 2006 Adis Data Information BV. All rights reserved.

Selective Phosphodiesterase (PDE)-4 Inhibitors A Novel Approach to Treating Memory Deficit? Afshin Ghavami,1 Warren D. Hirst1 and Thomas J. Novak2 1 2

Neuroscience Discovery Research, Wyeth Research, Monmouth Junction, New Jersey, USA Discovery Sciences and Technologies, Roche Palo Alto, Palo Alto, California, USA

Contents Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63 1. Phosphodiesterase-4 (PDE4) Inhibitors Improve Synaptic and Cognitive Functions in Rodent Models of Cognition and Alzheimer’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64 2. PDE4 Inhibitors Have Anti-Inflammatory as Well as Neuroprotective and Neuroregenerative Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 3. Potential Adverse Effects of PDE4 Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66 4. Current Clinical Development Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68

Abstract

Phosphodiesterase-4 (PDE4) belongs to an important family of proteins that regulates the intracellular level of cyclic adenosine monophosphate (cAMP). Several lines of evidence indicate that targeting PDE4 with selective inhibitors may offer novel strategies in the treatment of age-related memory impairment and Alzheimer’s disease. The rationale for such an approach stems from preclinical studies indicating that PDE4 inhibitors can counteract deficits in long-term memory caused by pharmacological agents, aging or overexpression of mutant forms of human amyloid precursor proteins. In addition to their pro-cognitive and pro-synaptic plasticity properties, PDE4 inhibitors are potent neuroprotective, neuroregenerative and anti-inflammatory agents. Based on the fact that Alzheimer’s disease is a progressive neurodegenerative disorder that is characterised by cognitive impairment, and that neuroinflammation is now recognised as a prominent feature in Alzheimer’s pathology, we have concluded that targeting PDE4 with selective inhibitors may offer a novel therapy aimed at slowing progression, prevention and, eventually, therapy of Alzheimer’s disease.

Alzheimer’s disease (AD) is a neurodegenerative condition that affects primarily hippocampal and neocortical brain regions resulting in a progressive loss of cognitive and memory function and ending ultimately in dementia. It is believed that accumulation of amyloid β (Aβ) peptides in the brain initiates

the pathological cascade leading to neurodegeneration in AD.[1] According to this amyloid cascade hypothesis, deposits of Aβ are responsible for causing tau phosphorylation and neurofibrillary tangle formation leading to neuronal death and dementia. However, the exact mechanism by which Aβ causes

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neurodegeneration is unclear. To explain neuronal cell death in AD patients, a modified, extended version of the amyloid cascade hypothesis called the amyloid cascade/neuroinflammation hypothesis has been proposed. According to this hypothesis, Aβ activates microglia cells, which produce neurotoxic substances, such as reactive oxygen and nitrogen species, proinflammatory cytokines, complement proteins and other inflammatory mediators, causing neurodegeneration.[2] Despite intensive research and development efforts by the pharmaceutical industry, to date no compounds that cure AD (AD disease modifiers) have been developed. However, two classes of drugs have been approved by the US FDA for the symptomatic treatment of AD – acetylcholinesterase inhibitors (donepezil, rivastigmine and galantamine) and the NMDA receptor antagonist memantine. These drugs work by increasing cholinergic activity and preventing glutamate toxicity, respectively, but do not affect disease progression. In addition, clinical use has suggested that they do not provide long-lasting relief from the ravages of AD. Given these limitations, alternative approaches are needed. This article provides an overview of data supporting the use of phosphodiesterase-4 (PDE4) inhibitors, which have pro-cognitive, anti-inflammatory and neuroregenerative properties, as a new class of drugs for the treatment of AD and related dementia. 1. Phosphodiesterase-4 (PDE4) Inhibitors Improve Synaptic and Cognitive Functions in Rodent Models of Cognition and Alzheimer’s Disease The process of memory formation in metazoans can be divided into at least two phases: short-term memory, which is independent of protein synthesis, and long-term memory, which requires both transcription and translation.[3,4] One form of synaptic plasticity that has received much attention as a model for learning and memory is hippocampal long-term potentiation (LTP), which is an activitydependent form of synaptic enhancement that, like long-term memory, requires new protein synthesis. Like many forms of memory and synaptic plasticity,  2006 Adis Data Information BV. All rights reserved.

LTP in the hippocampus has distinct temporal phases. The long-lasting, late phase of LTP (L-LTP) differs from the more transient early phase of LTP (E-LTP) in requiring cAMP elevation, protein kinase A (PKA) activation, protein synthesis and transcription.[5] One of the nuclear targets of PKA is the cAMP response element binding protein (CREB), a constitutively expressed transcription factor that activates transcription after phosphorylation of serine 133, a site phosphorylated by PKA as well as other kinases.[6,7] The importance of activation of the cAMP/CREB pathway, in both L-LTP and longterm memory, has been demonstrated in rodent models that either lacked or overexpressed one of the components of this pathway. For example, behavioural studies in mice either lacking isoforms of CREB[8] or overexpressing a truncated version of CREB-binding protein (CBP; cAMP response element binding protein-binding protein)[9] have suggested that this transcription factor plays a role in long-term memory storage. It has also been shown that downregulation of PKA activity in mice impairs both LTP and long-term memory.[10] Finally, a recent report showed that transgenic mice overexpressing type-1 adenylyl cyclase, which results in increased cAMP production in the brain, had enhanced memory and elevated LTP.[11] These and other studies clearly demonstrate that the cAMP pathway plays a key role in the induction of longterm neuronal and behavioural changes in Drosophila (fruit fly),[4,12] Aplysia (marine snail),[13,14] the honey bee[15,16] and mice.[10,11] Rolipram, a selective inhibitor of PDE4, produces an increase in brain cAMP levels by inhibiting its degradation.[17] Studies have shown that rolipram produces memory-enhancing effects in a number of models and has antidepressant-like activity in both preclinical[18] and clinical models.[19-21] For instance, rolipram and related drugs reverse the amnesic effects of scopolamine[22] (an anticholinergic agent), MK-801[23,24] (an NMDA antagonist), and U0126[25] (a mitogen-activated protein kinase inhibitor) on working and reference memory of rats tested in an eight-arm radial maze. Similarly, rolipram reverses memory deficits in a stroke model in rats.[26] Finally, Drugs R D 2006; 7 (2)

Selective PDE4 Inhibitors

rolipram facilitates LTP in hippocampal slices.[17] At the molecular level, rolipram, like many marketed antidepressants, increases expression of brainderived neurotrophic factor,[27,28] and increases proliferation of neural progenitor cells in the hippocampus.[27,29] Given the fact that cognitive deficits are a core component of depression, it is likely that the memory-enhancing effects of PDE4 inhibitors contribute, to some degree, to their overall antidepressant activity. Recent studies using animal models of amyloid deposition showed that overexpression of mutant forms of human amyloid precursor protein (APP) results in deficits in hippocampal synaptic plasticity (as measured by LTP), learning and memory.[30-33] Interestingly, these deficits are not always associated with neuronal loss, suggesting that cognitive decline due to overexpression of Aβ might be caused by dysfunction of neurons and synapses in selective brain regions.[34-38] Indeed, recent studies have identified impairment of both LTP and PKA/ CREB pathway signaling pathways following Aβ treatment both in hippocampal neurons in cultures[39] and in transgenic mice carrying both the mutant APP and presenilin-1 (PS-1) transgenes (APP/PS-1 mice).[34] Interestingly, impairment of both cognition and LTP in APP/PS-1 mice was reversed by either acute or chronic treatment with rolipram.[34] A very important and surprising finding from this study was the long-lasting effect of rolipram. After treatment of transgenic APP/PS-1 mice with rolipram for 3 weeks, deficits in basal transmission, LTP and different forms of explicit learning, including associative, working and reference memory defects, were ameliorated for up to 2 months compared with vehicle-treated animals. Interestingly, the beneficial effects of rolipram on synaptic physiology and behaviour of APP/PS-1 mice are not due to changes in Aβ40 and Aβ42 levels, since treatment with rolipram does not interfere with Aβ production or processing. The effect of rolipram appears to result from stabilisation of synaptic circuits via re-activation of the CREB pathway, which in untreated APP/PS-1 mice was shown to be significantly decreased.[34]  2006 Adis Data Information BV. All rights reserved.

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2. PDE4 Inhibitors Have Anti-Inflammatory as Well as Neuroprotective and Neuroregenerative Properties Considerable evidence supports the conclusion that neuroinflammation is associated with the pathogenesis of AD.[2,40,41] Exposure to Aβ causes activation of microglia,[42,43] leading to an increase in cell surface MHC class II expression along with increased secretion of reactive oxygen species and proinflammatory cytokines, which in turn leads to further neuronal damage.[2,44] It has been shown that a high level of activated microglia, with an anatomical distribution correlating to regions affected by AD pathology (the entorhinal, temporoparietal and cingulate cortices), can be detected in the brain of AD patients.[45] Interestingly, follow-up of these patients with serial magnetic resonance imaging (MRI) scans over the subsequent 12–24 months showed that the areas with the highest level of activated microglia had the highest rate of atrophy.[45] Thus, inflammation appears to be an early event in the pathogenesis of AD. Several studies have clearly demonstrated that rolipram and other PDE4 inhibitors possess potent anti-inflammatory effects in a variety of both in vitro and in vivo models.[46,47] For instance, chronic treatment with rolipram has been shown to inhibit lipopolysaccharide (LPS)-induced production of tumour necrosis factor (TNF)-α in the rat brain, at both the mRNA and the protein levels.[48] Another recent study reported that treatment of microglia cells in culture with Aβ resulted in both an upregulation of PDE4B isoform and an increase in TNF-α production, suggesting that PDE4B activation plays a central role in microglial activation in response to Aβ. Interestingly, rolipram effectively blocked Aβinduced microglial activation by decreasing TNF-α mRNA and the release of TNF-α.[49] These studies, together with immunohistochemical experiments showing an increase in TNF-α localised at senile plaques[50] and studies suggesting that TNF-α is essential for Aβ-induced inflammation,[51,52] suggest that treatment with PDE4 inhibitors might slow the progression of AD. Drugs R D 2006; 7 (2)

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Likewise, compounds that enhance regeneration might be beneficial for the treatment of AD and other neurodegenerative diseases. Unfortunately, most transgenic AD models overexpressing mutant forms of human APP, either alone or together with presenilin, show little or no neuronal loss based on levels of pre- or postsynaptic markers.[34,37] However, other models such as spinal cord injury are useful for identifying interventions that would enable axons to regenerate across the injury site and into injured tissue. Interestingly, a recent study showed that rolipram, when applied directly to neurons in culture, overcame the inhibitory effects of myelinassociated glycoprotein (MAG), which is a major factor in preventing axonal growth.[53,54] Furthermore, administration of rolipram either alone or in combination with Schwann cell/embryonic stem cells grafts promotes axonal regeneration and myelination and enhances functional recovery in adult rats subjected to spinal cord injury.[54,55] Even though these studies reported that rolipram mediated axonal growth at a previous injury site and in a hostile environment, they do not allow the conclusion that this kind of treatment prevents neurons from dying in the brain of patients with AD. More studies are needed to support the role of PDE4 inhibitors as neuroregenerative agents within the scope of the pathophysiology of AD. As a first step, a study could be designed to demonstrate whether stabilisation of synaptic circuits via reactivation of the CREB pathway in APP/PS-1 mice by long-term treatment with rolipram would translate into an increase in synaptic boutons, which in untreated APP/ PS-1 mice were shown to be significantly decreased.[56] In summary, PDE4 inhibitors demonstrate cognitive enhancement, have neuroprotective/neuroregenerative and anti-inflammatory properties, and make synapses more robust and more resistant to the toxic effects of Aβ. All of the studies highlighted thus far support the idea that PDE4 inhibitors can be effective memory enhancers and provide a new and promising perspective on the treatment of AD.  2006 Adis Data Information BV. All rights reserved.

Ghavami et al.

3. Potential Adverse Effects of PDE4 Inhibitors Although selective PDE4 inhibitors, especially for the treatment of respiratory disease, have been pursued by pharmaceutical companies for the last 25 years, it remains a stubborn fact that not a single compound of this class has yet reached the market. Preclinically, the most worrying potential toxicity of PDE4 inhibitors is vasculopathy, presenting primarily as mesenteric arteritis.[57] This condition is characterised by inflammation, haemorrhage and necrosis of blood vessels. Mechanistically, arteritis is thought to result from haemodynamic changes that are produced by excessive and prolonged vasodilation of specific vascular beds. Mechanisms by which PDE4 inhibitors cause certain vessels to become targets of inflammation are unknown. In contrast to rats, non-human primates treated with PDE4 inhibitors generally do not show arteritis. For instance, cilomilast has been reported to produce medical necrosis of mesenteric arteries in rats but not primates.[58] This suggested that this pathology might be rodent-specific. However, a recent toxicology study found that high doses of SCH 351591, a specific PDE4 inhibitor, in Cynomolgus monkeys produced acute to chronic inflammation of small- to medium-sized arteries in many tissues.[57] Discovery of arteriopathy in monkeys, previously considered resistant to this toxicity, carries implications for human risk. However, no clinically relevant adverse effects of PDE4 inhibitors have been reported to date. In addition, theophylline, a nonspecific PDE inhibitor, produces medial necrosis of mesenteric vessels in rats, but patients treated for many years with this compound at bronchodilator doses show no clinically relevant effects.[59,60] Thus, it is not clear whether arteritis is a compound-specific or targetspecific adverse effect of PDE4 inhibitors, or whether these lesions are the result of direct drug-induced toxicity. Most of the published clinical studies on the toxicity of PDE4 inhibitors involve rolipram. Emesis, nausea and gastric acid secretion were the doselimiting effects of rolipram in clinical studies evaluating the antidepressant activity of this comDrugs R D 2006; 7 (2)


pound.[20,61,62] Even though the precise mechanism remains to be elucidated, studies suggest that both peripheral and central control centres, such as the area postrema, are responsible for the emetic effect of this compound. In order to improve rolipramrelated adverse effect profiles, efforts have focused on two approaches. One hinges on targeting one of the two unique conformers of PDE4,[63] and the other focuses on selectively targeting PDE4 subtypes.[64] One hypothesis that has developed over recent years is that the emetogenicity of rolipram is related to its ability to bind to the so-called high-affinity rolipram binding site (HARBS), which is one of two pharmacologically distinct conformational states of PDE4 isozymes. In an attempt to limit this adverse effect, many pharmaceutical companies have tried to synthesise ‘rolipram-like’ compounds that – unlike rolipram, which targets HARBS – primarily target the low-affinity rolipram binding site (LARBS). Among these second-generation compounds, the most clinically advanced are cilomilast and roflumilast. At the time of writing, cilomilast (Ariflo; GlaxoSmithKline, Philadelphia, PA, USA)1 has received an Approvable Letter from the FDA for chronic obstructive pulmonary disease, and roflumilast (Daxas; Altana, Constanz, Germany) is under review by European authorities for the same indication. However, like rolipram and most of the second-generation PDE4 inhibitors, these compounds may be dose limited by adverse effects before they reach maximal efficacy. Although the strategy of targeting LARBS has produced PDE4 inhibitors with a better therapeutic ratio for inflammatory disease,[65-67] this might not be a suitable approach for developing PDE4 inhibitors to treat CNS diseases. In fact, it has been shown that most PDE4 activity in the brain, in contrast to that associated with pro-inflammatory and immune cells, is in the high-affinity state.[68-70] Thus, it would appear likely that the high-affinity site in the brain mediates the psychopharmacological effects of PDE4 inhibitors. 1

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An alternative approach toward improving both tissue specificity and adverse-effect profile involves targeting individual PDE4 subtypes. Over 20 splice variants encoded by four PDE4 genes (PDE4 A–D) have been cloned in humans and rodents.[71] In situ hybridisation and immunodetection studies in the brains of humans, rodents and monkeys demonstrated a broadly overlapping but distinct expression pattern.[72,73] It is important to note that in squirrel monkeys and rodents the PDE4D subtype is expressed in emetic trigger zones, such as the area postrema, and in many structures of the medulla, suggesting the involvement of this isoform in a variety of autonomic functions, including emesis.[63] Although rolipram, the prototypical inhibitor, is highly selective for PDE4, it shows no preference for a particular PDE4 gene family. Thus, at therapeutic doses it inhibits all known PDE4 isozymes to a relatively similar degree. Moreover, by studying the effect of PDE4 inhibitors in a pharmacological model of emesis using both PDE4B and PDE4D knockout mice, it was suggested that emesis resulting from administration of non-selective PDE4 inhibitors might be due to selective inhibition of PDE4D.[64-66] Although developing inhibitors for individual PDE4 subtypes might be attractive, this strategy is not without its challenges. First, it is not clear whether inhibiting a single PDE4 subtype will have enough of an effect on total cellular cAMP metabolism to alter cell function. Second, the high sequence homology among the four subtypes, particularly within the catalytic domains, renders this kind of approach difficult. Indeed, very few PDE4 inhibitors have been reported to show significant subtype selectivity.[74] However, recent reports using scaffold-based drug design based on co-crystallography of not only different PDE isoforms but also among PDE4 subtypes (PDE4B and PDE4D) showed that this kind of approach could be used to develop potent, subtype selective inhibitors.[75,76] The biggest hurdle, however, in developing subtype- or isoform-specific PDE4 inhibitors for the treatment

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of AD is simply a lack of understanding of the critical procognitive targets. If the rich toxicology of PDE4 inhibitors is not enough of a challenge for drug developers, it should also be noted that not all data support the view that PDE4 inhibitors will be procognitive. A recent study from Amy Arnsten’s laboratory at Yale has shown that elevation of PKA signaling in aged rats and primates actually worsens prefrontal cortical cognitive functioning.[77] Although the study has yet to be replicated, there are several methodological issues that may account for the observed results. In rats, a non-hydrolysable cAMP analog was injected into the prefrontal cortex, which could cause a global activation of intracellular PKA. This may have very different effects from a selective inhibitor targeting a PDE4 isoform involved in localised signaling.[78] Results with aged rhesus monkeys are more difficult to dismiss. Systemic administration of rolipram caused cognitive impairment in a spatial memory task at doses that did not cause sedation.[78] However, in these studies no attempt was made to determine the effect of rolipram on brain cAMP levels. This is an important point as studies with rodents have shown that rolipram can reverse scopolamineinduced deficits in working memory[79] at concentrations that do not appreciably elevate brain cAMP levels.[80] Thus, it may be possible to find a drug dose that improves hippocampal memory in patients while sparing prefrontal cortical function. Clearly, more work needs to be done on the impact of PDE4 inhibitors on different cognitive domains in both aged and diseased animal models. It is likely that definitive data, one way or the other, will have to await controlled clinical trials in patients with AD. 4. Current Clinical Development Activity Several companies are actively trying to develop PDE4 inhibitors for the treatment of cognitive disorders, but at present only one, Helicon Therapeutics, has a compound in the clinic. Helicon’s PDE4 inhibitor, HT-0712, entered phase 1 clinical trials in December 2004. The company has not publicly announced its target patient population but has done extensive work on the utility of PDE4 inhibitors in  2006 Adis Data Information BV. All rights reserved.

treating memory defects in Rubenstein-Taybi syndrome, a genetic disorder caused by mutations in the CREB-binding protein, CBP.[81] However, if HT-0712 advances beyond phase 1 it is likely that it will eventually be evaluated in AD patients. Memory Pharmaceuticals and Roche have been collaborating since 2002 to develop PDE4 inhibitors for various psychiatric and neurological indications. Memory recently announced that they have reacquired from Roche the rights to MEM1414, their lead clinical candidate for the symptomatic treatment of AD, after Roche discontinued development in April 2005. No reason for the discontinuation was given, but the companies are reportedly continuing to evaluate backup molecules. There is no doubt that there is extensive preclinical data supporting the use of PDE4 inhibitors for the symptomatic treatment of AD. Equally exciting are the recent data in mouse AD models suggesting that these compounds could also have disease-modifying effects. However, given the difficult development history of these compounds, it may be some years before clinical validation is obtained. Acknowledgements AG and WDH are employees of Wyeth, a pharmaceutical company exploring new therapies for Alzheimer’s disease. TJN is an employee of Roche Palo Alto, a pharmaceutical company actively trying to develop PDE4 inhibitors for the treatment of Alzheimer’s disease.

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Correspondence and offprints: Dr Afshin Ghavami, Neuroscience Discovery Research, Wyeth Research, 865 Ridge Road, Monmouth Junction, NJ 08852-2718, USA. E-mail: [email protected]

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