cAMP-specific phosphodiesterase inhibitors: promising drugs for inflammatory and neurological diseases.

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Review

cAMP-specific phosphodiesterase inhibitors: promising drugs for inflammatory and neurological diseases

1.

Introduction

2.

PDE4 inhibitors

3.

PDE7 inhibitors

Ana Martinez & Carmen Gil†

4.

PDE8 inhibitors

Centro de Investigaciones Biolo´gicas (CSIC), Madrid, Spain

5.

Expert opinion

Introduction: PDEs are key enzymes in the adenosine and guanosine cyclic nucleotides (cAMP and cGMP) signaling cascade. Their inhibition increases cyclic nucleotide levels inside the cell. Thus, pharmacological modulation of PDE activity can have profound effects on the function of cells and organ systems throughout the body. Areas covered: Among the large PDE families, only PDE4, PDE7 and PDE8 are cAMP-specific hydrolyzing enzymes. cAMP is an important second messenger not only by its involvement in a vast number of physiological processes but also by activation of protein kinase A, exchange protein activated by cAMP (Epac) and cAMP response element-binding (CREB) or cyclic nucleotide-gated channels. Clearly, such enzymes represent ideal drug targets for the pharmacological treatment of many pathologies. The discovery and development of small molecules targeting cAMP-specific PDEs reported in the last 5 years is the focus of the present review. Expert opinion: The first PDE4 inhibitors recently reached the market, having avoided, by different strategies, their dose-limiting side effects (after more than two decades of drug development). Meanwhile, new cAMP-specific PDE7 and PDE8 inhibitors emerged as effective and safe drugs for severe unmet diseases. The therapeutic potential of these inhibitors will be tested in the near future, as many of these drug candidates are ready to start clinical trials. Keywords: cAMP, PDE inhibitors, PDE4, PDE7, PDE8 Expert Opin. Ther. Patents [Early Online]

1.

Introduction

The cAMP signaling system was discovered more than half a century ago [1]. This nucleotide is able to convert the signal of a large variety of extracellular stimuli into specific cellular responses. In fact, cAMP is a second messenger that regulates many diverse cellular functions, including gene transcription, cell migration, mitochondrial homeostasis, cell proliferation and cell death [2]. cAMP is generated from ATP through the action of adenylyl cyclase, whereas PDEs hydrolyze this second messenger to its inactive 5¢-monophosphate. The only way to inactivate cAMP is to degrade it through the action of PDEs. These enzymes are able to degrade not only cAMP but also cGMP. Up to now, eleven human PDE families are known. They present different selectivity for cAMP or cGMP and possess different intracellular distributions and catalytic/regulatory properties [3,4]. Among the large PDE families, only PDE4, PDE7 and PDE8 are cAMP-specific, whereas PDE5, PDE6 and PDE9 are specific for cGMP. The remaining PDE families hydrolyze both cyclic nucleotides [5]. As the imbalance of cAMP in inflammatory cells can lead to several inflammatory disorders, great efforts in the last two decades have 10.1517/13543776.2014.968127 © 2014 Informa UK, Ltd. ISSN 1354-3776, e-ISSN 1744-7674 All rights reserved: reproduction in whole or in part not permitted

1

A. Martinez & C. Gil

PDE7 and PDE8 inhibitors and their potential as drug candidates for human unmet diseases.

Article highlights. .

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Pharmacological modulation of cAMP levels through PDE activity is a good therapeutic strategy to alleviate several diseases in which inflammation plays a critical role. Only PDE4, PDE7 and PDE8 are cAMP-specific hydrolyzing enzymes. Although the therapeutic potential of PDE4 inhibitors has been widely reported, the dose-limiting side effects, such as nausea and emesis, have significantly delayed their clinical success. New research strategies, such as targeting PDE7 and/or PDE8, are in progress to develop compounds able to increase cellular cAMP levels but with a reduced side-effect profile. Development of PDE7 and PDE8 inhibitors alone or in combination with PDE4 inhibitors may provide innovative pharmacological therapies for severe unmet diseases.

This box summarizes key points contained in the article.

been devoted to the discovery and development of PDE4 inhibitors as pharmacological agents [6]. Small molecules targeting PDE4, such as rolipram, have shown promising results in preclinical models of different inflammatory diseases, but success in the clinical development of PDE4 inhibitors has been limited due to a number of dose-limiting side effects, such as nausea and emesis [7]. The mechanism by which PDE4 inhibition results in these adverse gastrointestinal effects is not fully understood but probably includes both central and peripheral sites of action. In fact, the human area postrema and other nuclei related to the emetic reflex express PDE4B and 4D [8]. Moreover, the emetic effect of PDE4 inhibitors is caused, at least in part, via binding to the high-affinity rolipram binding site (HARBS) in the brain in vivo [9]. Roflumilast, the first marketed PDE4 inhibitor, was approved in Europe in 2010 and in the USA in 2011 as an oral add-on treatment for chronic obstructive pulmonary disease (COPD) patients [10]. Since then, other PDE4 inhibitors have progressed in clinical development (reviewed in [11]). A second oral small-molecule inhibitor of PDE4, apremilast, has been recently approved in the USA for the treatment of active psoriatic arthritis [12,13], while the PDE4 inhibitor ASP9831 failed in Phase II trials due to the lack of efficacy in non-alcoholic steatohepatitis [14]. In addition, new research strategies are in progress to develop compounds able to increase cellular cAMP levels with a reduced side-effect profile. These include development of subtypeselective and non-brain penetrant PDE4 inhibitors, compounds with a reduced affinity for HARBS, or allosteric enzyme inhibitors [15]. Another strategy is the inhibition of different cAMP-specific PDEs, such as PDE7 and/or PDE8 [16,17], the new emerging targets in the field. This review will be focused specifically on cAMP-specific PDE4, 2

2.

PDE4 inhibitors

The PDE4 inhibitor family has attracted considerable attention in the last decade, because of their potential therapeutic uses in a range of major disease areas where inflammation plays a severe pathological role [18-21]. PDE4 enzymes specifically hydrolyze cAMP and are encoded by four distinct genes (PDE4A--PDE4D). Their isoforms show distinct and specific cell-type patterns of expression and distribution, and they play major regulatory roles in many cell types and tissues, including leukocytes, airway and vascular smooth muscle, vascular endothelium and the brain [5,22]. The involvement of PDE4 in pathological processes associated with these tissues suggests a great potential for pharmacological intervention in a large variety of disorders, such as inflammatory and neurological pathologies, through modulation of cAMP levels [23-27]. In fact, a number of PDE4 inhibitors have reached clinical trials for the treatment of inflammatory diseases [22,28]. Despite the failure of most of them because of side effects, such as emesis and nausea, roflumilast was approved in 2011 for the treatment of COPD [29] and apremilast received its approval in 2014 as the first target-specific oral psoriasis drugs (Figure 1) [30,31]. Although both are pan-inhibitors of PDE4A--4D, they have demonstrated that it is possible to achieve an improved therapeutic window. The improved tolerability of roflumilast is due to a suitable pharmacokinetic profile without a sharp Cmax [32], while the reason why apremilast has reduced emetic effects is not yet disclosed [33]. All these facts have maintained the interest in the development of new drugs targeting PDE4, and several small molecules have been patented over the past 5 years as PDE4 inhibitors. The inventions cover the preparation thereof, composition of them, combinations and therapeutic uses thereof. Most of them are claimed to be good anti-inflammatory agents based on the well-known relationship between cAMP levels and inflammatory processes. The range of diseases is huge, and due to the recently approval of roflumilast as treatment for COPD, most of the recently disclosed patents are focused on airway diseases. The avoidance of gastrointestinal effects is the main issue in this second generation of PDE4 inhibitors, and administration via inhalation has been one of the strategies used [26]. As representative examples of the new chemical structures (Figure 2), Chiesi Farmaceutici produced different series of 1-phenyl-2-pyridinyl alkyl alcohols (I [34], II [35] and III [36]) for the treatment of different pulmonary diseases after inhaled administration [37]. The most advanced candidate of these series, named CHF 6001, has reached clinical trial Phase II for asthma and COPD treatment [38]. CHF 6001 is a novel selective PDE4 inhibitor, optimized for inhaled delivery to improve efficacy and tolerability. The anti-inflammatory activity of CHF 6001 has been proven in vitro and in several

Expert Opin. Ther. Patents (2014) 24(12)

cAMP-specific phosphodiesterase inhibitors

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Figure 1. PDE4 inhibitors on the market.

animal models of airway inflammation, showing higher potency than roflumilast and more targeted anti-inflammatory effects than corticosteroids in COPD models [37]. Moreover, these compounds can also be used as coadjuvant in leukemia treatment [39]. Almirall recently claimed that heterocyclic compounds, such as 7,8-dihydro-1,6-naphthyrydin-5(6H)-one derivatives (IV [40]), are potent PDE4 inhibitors with IC50 values in the subnanomolar range and have the ability to decrease TNF-a levels. Other heterocyclic compounds, such as 5substituted-1,4-benzodiazepines (V [41]), benzo-fused heterocycles (VI [42], VII [43], VIII [44]), triazolopyridazines (IX [45]), triazolopyridines (X [46]), pyrimidinone derivatives (XI [47]) or biaryls (XII [48]) used alone or in combination with other known drugs, have also been recently claimed to be effective in the treatment of a variety of disorders involving inflammatory states, such as asthma, COPD, rheumatoid arthritis, autoimmune pathology and neurological disorders, such as depression, Parkinson’s and Alzheimer’s disease. However, nothing has been reported about the potential emetic side effects even when CNS diseases are claimed as the target for these compounds. Emesis has been shown to be a dose-limiting side effect. Thus, the selective PDE4D inhibitor, GEBR-7b, is able to improve memory in rodents at non-emetic doses due to the relatively low doses required to improve memory [49]. Moreover, allosteric PDE4D modulators have reduced potential to cause emesis because they do not completely inhibit enzyme activity while maintaining efficacy [15]. Another potential alternative used to overcome the doselimiting side effects of PDE4 inhibitors is to develop new chemotypes that target other members of the cAMPdependent family, such as PDE7, which is also distributed in almost all pro-inflammatory and immune cells [50]. This is the strategy claimed by Ranbaxy Laboratories Limited to design their nitrogen heterocycle dual inhibitors of PDE4 and PDE7 (XIII [51]). It is expected that these dual inhibitors may achieve a higher therapeutic index and thereby exhibit a

lower propensity to cause adverse side effects that are characteristic when targeting PDE4 alone [52]. Another alternative to overcome the PDE4 emetogenic side effects is the development of soft drugs that are inactivated early in the blood for the local treatment of inflammatory diseases, such as the drugs disclosed by Amakem NV for the treatment of dry eye disease (XIV [53]). Finally, it is worth mentioning that in addition to Chiesi Farmaceutici’s inhibitor, other PDE4 inhibitors have entered clinical development in the last 5 years (Figure 3). Two compounds from GlaxoSmithKline, GSK356278 and GSK25 6066, are in clinical trials Phase I and II, respectively. GSK356278 [54,55], which inhibits PDE4A, PDE4B and PDE4D enzyme activity with a pIC50 of 8.6, 8.8 and 8.7, respectively, and binds the high-affinity rolipram-binding site, has shown anxiolytic effects in common marmosets and enhances performance in a model of executive function in cynomolgus macaques with no adverse effects at the doses tested. This therapeutic profile, together with the good data in clinical Phase I, supports further evaluation of GSK3 56278 in patients for depression, anxiety and Huntington’s disease [56]. Although studies have now been completed, results are not yet available. Regarding GSK256066, the safety and tolerability of this intranasally administered PDE4 inhibitor has been reported [57], while its efficacy in COPD and seasonal allergic rhinitis patients is under study [58]. Merck also has one PDE4 inhibitor in clinical development. The 8-biarylnaphthyridinone called MK0952 was discovered with the aim of penetrating into the brain through the blood--brain barrier [59]. This compound showed benefits in animal models for long-term memory and mild cognitive impairment and is currently in clinical trials for mild-tomoderate Alzheimer’s disease [60]. This study finished in 2013 but the results are not yet available. Dart NeuroScience LLC has conducted clinical trials of a PDE4 inhibitor named HT-0712 [61]. As the preclinical data in a model of focal ischemia showed a cortical reorganization [62] and improvement in hippocampus-dependent memory in aged mice after HT-0712 administration [63], a Phase IIa study is being carried out in elderly subjects with age-associated memory impairment [61]. Topical administration of PDE4 inhibitors for the treatment of dermatological diseases, such as atopic dermatitis, is also being tested on humans [64]. That is the case of Anacor, which is the sponsor of the clinical development of AN2728, a novel boron-containing small molecule that reduces the production of TNF-a by inhibition of PDE4. Other cytokines, including IL-12 and IL-23, which are proteins believed to be involved in the inflammation process and immune response, presented reduced levels after treatment with AN2728 [65]. Because AN2728 has demonstrated safety in 18 clinical trials, it is expected to become a safe and effective treatment option for patients who suffer from atopic dermatitis and that it could potentially be combined with topical corticosteroids and vitamin D analogs for patients with


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Figure 2. Patented PDE4 inhibitors during the period 2009 -- 2013.

mild-to-moderate psoriasis. The Phase III study in mild-tomoderate atopic dermatitis started in March 2014, and it is expected to produce the final results in the first half of 2015 [66]. 3.

PDE7 inhibitors

The second cAMP-specific PDE discovered was PDE7 [67]. This isoenzyme is encoded by two genes, PDE7A and PDE7B. High mRNA concentrations of both PDE7A and PDE7B are found in rat brains and in numerous peripheral 4

tissues, although the distribution of these enzymes at the protein level has not been reported [68]. Within the brain, PDE7A mRNA is abundant in the olfactory bulb, hippocampus and several brain-stem nuclei [69]. The highest concentrations of PDE7B transcripts in the brain are found in the cerebellum, dentate gyrus of the hippocampus and the striatum [70,71]. There is very little information regarding the physiological functions that are regulated by PDE7, although its transcriptional activation through the dopamine receptor D1 is well documented [72]. It has been shown that PDE7 is involved in pro-inflammatory processes and is necessary for the



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Figure 3. PDE4 inhibitors in clinical trials.

induction of T-cell proliferation [73]. Moreover, an increase in PDE7B expression in chronic lymphocytic leukemia has been described [74]. In a previous comprehensive review article, a number of chemically diverse PDE7 inhibitors were shown and the development of inhibitors of PDE7 was reported as a new approach to be explored for the treatment of neurological and inflammatory disorders due to the increasing levels of cAMP [75]. In the last 5 years, several methods have been developed for the discovery of PDE7 inhibitors [16,76,77] because great interest in them emerged as a way to overcome the side effects of PDE4 inhibitors [78]. These new compounds provide useful pharmacological tools for the assessment of the physiological and pathological function of PDE7 in different cellular and animal models. Several new and diverse chemical structures have been recently reported, such as thioxoquinazolines [79], quinazolines [80] and pyrimidine derivatives [81]. Moreover, some of them are emerging as valuable clinical candidates [82], while the potential benefit of their concomitant administration with a PDE4 inhibitor has been recently reported [83] (see also Ranbaxy patent [51]). The pharmacological profile of one heterocyclic smallmolecule inhibitor of PDE7 called S14, which belongs to a new family of quinazoline derivatives patented by CSIC (Figure 4) (XV [82]), has been well studied, mainly for neurological disorders. First, a detailed theoretical and experimental study of the mechanism of PDE7 inhibition by the quinazoline S14 reveals that it is a specific and allosteric modulator [84], providing a subtle modulation of cAMP homeostasis with great beneficial effects in animal models. S14 conferred significant neuronal protection against different insults both in the human dopaminergic cell line SH-SY5Y and in primary rat

mesencephalic cultures. S14 treatment reduced microglial activation and improved motor function in the lipopolysaccharide rat model of Parkinson’s disease (PD) [85] and in a model of spinal cord injury [86]. The efficacy of S14 is abolished by blocking the cAMP signaling pathways that operate through cAMP-dependent protein kinase A. These results show that inhibition of the PDE7 enzyme leads to dopaminergic neuronal protection and, therefore, its inhibitors may exert useful therapeutic actions in patients with PD by modifying the course of the neurodegenerative process [87]. Additionally, the neuroprotective effects of S14 are present in a model of Alzheimer’s disease, and thus, S14 is a good candidate for further development with the aim of reaching clinical trials [88]. More recently, the adequate CNS penetration of a different PDE7 inhibitor belonging to the imidazopyridazinone family in mice allowed it to be tested in the MPTP-induced PD model and haloperidol-induced catalepsy model, probing the differential pharmacology of PDE7 in the striatal pathway [89] and confirming the utility of this new class of drugs for the treatment of PD [87]. In fact, Omeros has claimed the use of several diverse PDE7 inhibitors for the treatment of different movement disorders, such as PD, among others [90]. It is noteworthy that cAMP is involved in the differentiation of several cell lines or stem cells into dopamine neurons [91], which is considered a promising strategy for cell replacement therapy in PD. Recently, it has been shown that the quinazoline PDE7 inhibitor S14 is able to promote differentiation of stem cells isolated from the adult rat hippocampus and from the subventricular zone into tyrosine hydroxylasepositive mature neurons [92]. Furthermore, S14 promotes new neurogenesis in the substantia nigra after the administration of 6-OHDA.


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Figure 4. Quinazoline- and iminothiadiazole-like PDE7 inhibitors.

Finally, CSIC has also claimed other different chemotype for targeting PDE7: the 5-imino-thiadiazole family (Figure 4) (XVI [93]). These compounds produce a decrease in the inflammatory reaction in a spinal cord injury model [86] and induce neuronal in vivo neuroprotection [94]. The enhancement of oligodendrocyte precursor survival and their differentiation promoted by PDE7 inhibitor treatment is promising. These important properties may facilitate the therapeutic remyelination strategies for the treatment of multiple sclerosis [95]. Moreover, the therapeutic potential of PDE7 inhibitors for multiple sclerosis has been unequivocally assessed in murine experimental allergic encephalomyelitis models with treatment with chemically diverse PDE7 inhibitors [96-98]. This fact opens a new and promising therapeutic strategy for the future treatment of this neurological disease. Recently, crosstalk between PDE7 and glycogen synthase kinase 3, a key target in neurological pathologies, has been described, thus increasing the potential of these cAMPspecific PDE inhibitors in the treatment of many unmet diseases [99]. Overall, inhibition of PDE7 is a good strategy to modulate cAMP with its beneficial effects in dopaminergic cell protection and decreased neuroinflammatory activation, and also because of the lack of gastrointestinal side effects [100,101], such as those produced by PDE4 inhibitors. This makes the PDE7 inhibitors good drug candidates for CNS diseases and especially for PD and multiple sclerosis.

of PDE8B could be an interesting therapeutic intervention to enhance memory and motor function [115]. In addition, overexpression of brain protein levels of PDE8 has been recently associated with age, confirming the pharmacological interest of its inhibitors for the treatment of age-associated diseases [116]. However, only a few PDE8-selective inhibitors are available, and thus, there is an urgent need not only to explore the physiological and pathological role of PDE8 but also to develop them for clinical trials of human disease. The particular structures of these PDEs suggest that specific drugs for PDE8 might be developed [17]. In fact, the recent development of a new PDE8 inhibitor by Pfizer, named PF-4957325 [117], has helped to identify PDE8 as a novel target for suppression of effector T-cell functions due to the important role of the PDE8 family in regulating cAMP signaling in these cells. Until the discovery of this new inhibitor, only dipyridamole was used experimentally to study the cellular roles of PDE8, even though it is a nonselective inhibitor. Due to the lack of PDE8 inhibitors and the potential of this target, high-throughput screening (HTS) campaigns were carried out by Pfizer with the aim of discovering new hits that will allow an in-depth study of the PDE8 function and further development of its inhibitors (Figure 5). Of particular interest were the hits found based on tetrahydroisoquinoline [118] or triazolopyrimidine [119] scaffolds, which have been the starting points of medicinal chemistry programs to increase potency and selectivity [120]. The utility of PDE8 inhibitors alone or in combination with PDE4 or PDE7 inhibitors has also been claimed to treat inflammation and immune-related disorders by the University of Connecticut [121], and a cell-based HTS was developed to detect PDE8 inhibitors and PDE4/PDE8 inhibitors combination. By using this methodology, the dual-inhibitor BC8-15was discovered and supported the proposal that this combination might be a good therapeutic candidate to elevate steroidogenesis in Leydig cells [122]. 5.

4.

PDE8A and PDE8B exhibit a high-affinity cAMP-specific PDE activity that was not inhibited by various PDE inhibitors, including IBMX (3-isobutyl-1-methylxanthine) [102-104]. PDE8A is expressed in Leydig cells in the testes [105] and also in cardiomyocytes [106], whereas PDE8B is found in the thyroid gland [107], brain [107,108] and adrenal gland [109]. The biological function of PDE8 is still unknown, although based on its pattern of expression it is possible to speculate an important physiological role in different processes, including testosterone production, thyroid function or cognitive disorders. Based on this, a PDE8 inhibitor could be useful as a treatment of thyroid dysfunction [110] and modulation of steroidogenesis in the testes and adrenal glands [111-113]. Moreover, as overexpression of PDE8B mRNA is observed in the brains of Alzheimer’s patients [114], partial inactivation 6

Expert opinion

PDE8 inhibitors Enhancing intracellular cAMP levels may be a good therapeutic strategy to alleviate several diseases in which inflammation plays a critical role, such as some pulmonary, dermatological and severe neurological diseases. cAMP-specific PDEs, PDE4, PDE7 and PDE8, are the enzymes responsible for cAMP degradation, and their inhibition produces an increase in intracellular cAMP levels. They are druggable targets, and their inhibitors have great therapeutic potential for several unmet disorders [123]. PDE4 inhibitors were the first compounds in clinical development after effective preclinical results, but the emetic side effect found in humans stopped or delayed the success of these clinical trials. However, roflumilast and apremilast have been approved in the last 2 years for the treatment of COPD and psoriasis. These drugs target PDE4 with an improved therapeutic window. Although the mechanism by which PDE4 inhibitors result in these side



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Figure 5. PDE8 inhibitors.

effects is not fully understood, several strategies to dissociate the beneficial and detrimental effects of PDE4 inhibitors have led to some degree of success, and the second generation of PDE4 inhibitors is on the way with better pharmacokinetics profiles. Different administration patterns, such as inhalation or topical administration, are being developed for PDE4 inhibitors. Moreover, compounds that simultaneously target other cAMP-specific PDEs, such as PDE7 or PDE8, are being testing to obtain new effective drugs with a better therapeutic window [78]. Some of these novel dual PDE7/ PDE4 inhibitors have been claimed by different groups [124], while a new antisense therapy targeting these two PDEs has shown efficacy in decreasing lung inflammation in mice [125,126]. In the meantime, PDE7 inhibitors emerged as a promising family of new anti-inflammatory drugs. They have proven efficacy in animal models of multiple sclerosis, Parkinson’s and Alzheimer’s diseases, while they have shown a decrease in the inflammatory reaction of a spinal cord injury model and stroke. Some companies, such as Omeros and Araclon, are involved in active development of PDE7 inhibitors to reach clinical trials. They are looking for innovative drugs for neurodegenerative diseases [82] and/or movement disorders [90]. PDE7 inhibitors have emerged as potent and effective drugs in preclinical models, offering good candidates to be future drugs with an apparent lack of emetic side effects. Finally, PDE8 inhibitors can be considered as a new opportunity to be explored as valuable drug candidates for neurological diseases, including Alzheimer’s disease and also

pathologies related to male fertility. Research has just started in this field, and the near future will see the results. In summary, enhancing cAMP intracellular levels that restore the endogenous homeostasis of this important second messenger that is lost in different unmet diseases is a good therapeutic approach for human diseases. As the only way to inactivate cAMP is to degrade it through the action of PDEs, cAMP-PDEs have emerged as promising therapeutic targets for inflammatory diseases as their inhibitors are innovative drugs to treat a great variety of pathologies. Different expression of these targets throughout the body may modulate the therapeutic potential of their inhibitors. While some PDE4 inhibitors have recently reached the market, only human clinical trials will confirm the great hope in the new PDE7 and PDE8 inhibitors as effective drugs for severe unmet diseases. Moreover, based on the promising preclinical studies reviewed here, we are confident in the clinical success of PDE7 inhibitors.

Declaration of interest The authors were supported by Financial support from MINECO and FEDER funds (EU program) (project nos. SAF2012-33600 and IPT-2012-0762-300000). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.


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Affiliation

Ana Martinez & Carmen Gil† Author for correspondence Centro de Investigaciones Biolo´gicas (CSIC), Ramiro de Maeztu 9, 28040 Madrid, Spain E-mail: [email protected] †

11

Phosphodiesterase-5 inhibitors: emerging nephroprotective drugs.

Inflammatory reaction in neurological diseases.

Neurological disorders and inflammatory bowel diseases.

Nonsteroidal anti-inflammatory drugs and prostatic diseases.

D-Arginine as a neuroprotective amino acid: promising outcomes for neurological diseases.

Aldosterone synthase inhibitors as promising treatments for mineralocorticoid dependent cardiovascular and renal diseases.

Phosphodiesterase 4 inhibitors and drugs of abuse: current knowledge and therapeutic opportunities.

Complement therapeutics in inflammatory diseases: promising drug candidates for C3-targeted intervention.

Lipids and neurological diseases.

Gangliosides and neurological diseases.

Clinical and preclinical treatment of urologic diseases with phosphodiesterase isoenzymes 5 inhibitors: an update.

Additive anti-inflammatory effects of corticosteroids and phosphodiesterase-4 inhibitors in COPD CD8 cells.

Journal Club: Phosphodiesterase-4 Inhibitors.

Evolution of Phosphodiesterase-5 Inhibitors.

[Treatment with phosphodiesterase inhibitors: Pro].

Mitochondrial Biology and Neurological Diseases.

Coenzyme Q10 and Neurological Diseases.

Targeting poly(ADP-ribose)polymerase1 in neurological diseases: A promising trove for new pharmacological interventions to enter clinical translation.

Radiopharmaceutical stem cell tracking for neurological diseases.

The role of phosphodiesterase inhibitors in the management of pulmonary vascular diseases.

Neutrophil elastase inhibitors: a patent review and potential applications for inflammatory lung diseases (2010 - 2014).

Discovery and development of Janus kinase (JAK) inhibitors for inflammatory diseases.

Letter: Drugs for rare diseases.

CD133-Positive Membrane Particles in Cerebrospinal Fluid of Patients with Inflammatory and Degenerative Neurological Diseases.