Search

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To evaluate the benefits and harms of PDE4 inhibitors (e.g., apremilast) for the treatment of PsA.

Atopic dermatitis (AD), a chronic, relapsing, inflammatory skin disease that is characterized by intense pruritus and eczematous lesions with up to 90% of patients presenting with mild to moderate disease. Current topical treatments for AD have not changed in over 15 years and are associated with safety concerns. In AD, overactivity of phosphodiesterase 4 (PDE4), leads to inflammation and disease exacerbation. Crisaborole Topical Ointment, 2%, is a novel, nonsteroidal, topical anti-inflammatory PDE4 inhibitor currently being investigated for the treatment of mild to moderate AD. Preliminary studies in children and adults demonstrated favorable efficacy and safety profiles. Crisaborole may represent an anti-inflammatory option that safely minimizes the symptoms and severity of AD and that can be used for both acute and long-term management.

In this study, catecholamides (7a–l) bearing different aromatic rings (such as pyridine-2-yl, pyridine-3-yl, phenyl, and 2-chlorophenyl groups) were synthesized as potent phosphodiesterase (PDE) 4 inhibitors. The inhibitory activities of these compounds were evaluated against the core catalytic domains of human PDE4 (PDE4CAT), full-length PDE4A4, PDE4B1, PDE4C1, and PDE4D7 enzymes, and other PDE family members. Eight of the synthesized compounds were identified as having submicromolar IC50 values in the mid-to low-nanomolar range. Careful analysis on the structure-activity relationship of compounds 7a-l revealed that the replacement of the 4-methoxy group with the difluoromethoxy group improved inhibitory activities. More interesting, 4-difluoromethoxybenzamides 7i and 7j exhibited preference for PDE4 with higher selectivities of about 3333 and 1111-fold over other PDEs, respectively. In addition, compound 7j with wonderful PDE4D7 inhibitory activities inhibited LPS-induced TNF-α production in microglia.

Le glaucome est la principale cause de cécité irréversible dans le monde. Chez les patients atteints de cette pathologie, la perte de la vue résulte de la mort sélective des cellules ganglionnaires (CGR) de la rétine ainsi que de la dégénérescence axonale. La pression intraoculaire élevée est considérée le facteur de risque majeur pour le développement de cette maladie. Les thérapies actuelles emploient des traitements pharmacologiques et/ou chirurgicaux pour diminuer la pression oculaire. Néanmoins, la perte du champ visuel continue à progresser, impliquant des mécanismes indépendants de la pression intraoculaire dans la progression de la maladie. Il a été récemment démontré que des facteurs neuroinflammatoires pourraient être impliqués dans le développement du glaucome. Cette réponse est caractérisée par une régulation positive des cytokines pro-inflammatoires, en particulier du facteur de nécrose tumorale alpha (TNFα). Cependant, le mécanisme par lequel le processus neuroinflammatoire agit sur la mort neuronale reste à clarifier. L’hypothèse principale de ce doctorat propose que les facteurs pro-inflammatoires comme le TNFα et la phosphodiestérase 4 (PDE4) interagissent avec les mécanismes moléculaires de la mort neuronale, favorisant ainsi la survie et la protection des CGRs au cours du glaucome. Dans la première partie de ma thèse, J’ai utilisé un modèle in vivo de glaucome chez des rats Brown Norway pour montrer que l’expression du TNFα est augmentée après l'induction de l'hypertension oculaire. L'hypothèse spécifique de cette étude suggère que les niveaux élevés de TNFα provoquent la mort des CGRs en favorisant l'insertion de récepteurs AMPA perméables au calcium (CP-AMPAR) à la membrane cytoplasmique. Pour tester cette hypothèse, j’ai utilisé un inhibiteur sélectif de la forme soluble du TNFα, le XPro1595. L'administration de cet agent pharmacologique a induit une protection significative des somas et des axones des neurones rétiniens. L'évaluation de la perméabilité au cobalt a montré que le TNFα soluble est impliqué dans l'insertion de CP-AMPAR à la membrane des CGRs lors du glaucome. L’exposition des neurones à une pression oculaire élevée est à l’origine de la hausse de la densité membranaire des CP-AMPARs, grâce à une diminution de l’expression de la sous-unité GluA2. La présence de GluA2 au sein du récepteur ne permet pas l’entrée du calcium à l’intérieur de la cellule. L'administration intraoculaire d’antagonistes spécifiques des CP-AMPARs promeut la protection des somas et des axones des CGRs. Ces résultats montrent que les CP-AMPARs jouent un rôle important dans la pathologie du glaucome. Dans la deuxième partie de ma thèse, j’ai caractérisé l'effet neuroprotecteur d’un inhibiteur de la PDE4, l’ibudilast, dans notre modèle de glaucome. L'hypothèse spécifique s’oriente vers une atténuation de la réponse neuroinflammatoire et de la gliose par l’administration d’ibudilast, favorisant ainsi la protection neuronale. Les résultats montrent que dans les rétines glaucomateuses, l’ibudilast diminue la gliose et l'expression de plusieurs facteurs tels que le TNFα, l'interleukine-1β (IL-1β), l’interleukine-6 (IL-6) et le facteur inhibiteur de la migration des macrophages (MIF). Chez les rats glaucomateux, nous avons observé une expression notable de PDE4A dans les cellules de Müller, qui est en corrélation avec l'accumulation de l’AMP cyclique (AMPc) dans ces cellules après un traitement d’ibudilast. Finalement, nous avons démontré que la protection des CGRs via l’administration d’ibudilast est un mécanisme dépendent de l’AMPc et de la protéine kinase A (PKA). En conclusion, les résultats présentés dans cette thèse identifient deux mécanismes différents impliqués dans la perte des CGRs au cours du glaucome. Ces mécanismes pourraient fournir des perspectives potentielles pour le développement de nouvelles stratégies de traitement du glaucome., Glaucoma is the leading cause of irreversible blindness worldwide. Loss of vision in glaucoma results from the selective death of retinal ganglion cells (RGCs) and axonal degeneration. Elevated intraocular pressure (IOP) is the major risk factor for developing glaucoma, and current therapies have focused on pharmacological or surgical strategies to lower IOP. However, visual field loss continues to progress in spite of effective pressure control, indicating that mechanisms other than elevated IOP contribute to disease progression. Recent data demonstrate a neuroinflammatory component in glaucoma, characterized by upregulation of proinflammatory cytokines, most notably tumor necrosis factor α (TNFα). However, the mechanism by which the neuroinflammatory response acts on RGC death needs to be clarified. The main hypothesis of this thesis is that targeting pro-inflammatory factors including TNFα and phosphodiesterase-type 4 (PDE4), interferes with molecular mechanisms that contribute to RGC death and this will thus successfully promote neuronal protection. In the first part of my thesis, I used an in vivo glaucoma model in Brown Norway rats to show that TNFα is upregulated early after induction of ocular hypertension. The specific hypothesis of this study is that high levels of TNFα promote RGC death by mediating the membrane insertion of Ca2+-permeable AMPA receptors (CP-AMPARs). I blocked TNFα function with XPro1595, a selective inhibitor of soluble TNFα. Administration of XPro1595 effectively protected RGC soma and axons. The cobalt permeability assay was used to show that soluble TNFα triggers the membrane insertion of CP-AMPAR in RGCs of glaucomatous retinas. This CP-AMPAR activation is caused by the downregulation of GluA2 which occurs when neurons are exposed to elevated IOP. Finally, intraocular administration of specific CP-AMPAR antagonists promoted RGC soma and axon protection. Taken together, these results show that CP-AMPARs play an important role in in the pathology of glaucoma. In the second part of my thesis, I characterized the neuroprotective effect of ibudilast, an inhibitor of PDE4, in the Brown Norway glaucoma model. We hypothesized that ibudilast promotes neuron protection by attenuating gliosis and the neuroinflammatory response. The results show that in glaucomatous retinas, ibudilast attenuates gliosis and the expression of TNFα, interleukin-1β (IL-1β), interleukin-6 (IL-6) and macrophage migration inhibitory factor (MIF). Interestingly, elevated IOP leads to substantial expression of PDE4A in Müller cells, which correlates with the accumulation of cAMP in these cells after ibudilast treatment. Lastly, ibudilast promoted RGC soma and axons protection through the activation of the cAMP/PKA pathway. In conclusion, the findings presented in this thesis identify two different mechanisms underlying RGC loss in glaucoma. These mechanisms can potentially provide new insights to develop novel strategies for the treatment of glaucoma

Introduction: Tetomilast is a novel thiazole phosphodiesterase-4 (PDE-4) inhibitor, which may prove useful in both the treatment of inflammatory bowel disease (IBD) and chronic obstructive pulmonary disease (COPD). Here, the authors review the pharmacology of the drug, and offer critical review of the available data for use of tetomilast in the treatment of IBD. Areas covered: Peer-reviewed publications, including Phase I and II clinical trials, all other formats included. Expert opinion: Tetomilast may be beneficial in IBD. Small differences in molecules and in recombinant proteins can translate into substantial differences in clinical effects and toxicity in IBD. This is a reasonable approach when exploring new options like tetomilast.

The nosology and treatment options for cognitive impairment in Parkinson disease (PD) remains perhaps the greatest unmet clinical need.1 The reported frequency of mild cognitive impairment (MCI) in newly diagnosed PD has ranged from 22% to 43%.2,3 A proportion of those with PD-MCI progress to PD dementia (PDD), the prevalence of which is variously estimated between 24% and 31%, but is as high as 75% in longitudinal studies.4 Dementia is associated with increased disability, nursing home placement, mortality, and caregiver stress. Global cognition and executive/working memory deficits also occur in individuals at risk for PD.5 Which features of MCI are predictive of development of dementia remain a matter of debate.

Resume Introduction La prise en charge medicamenteuse actuelle de la BPCO fournit des effets incompletement satisfaisants en termes d’amelioration des symptomes, de la tolerance a l’exercice, de la frequence des exacerbations et de la qualite de vie. Une explication possible serait que les traitements actuels ciblent mal les voies aeriennes distales (VAD), pourtant tres impliquees dans l’obstruction bronchique et ses consequences (distension…). Etat des connaissances De nombreux traitements utilises dans la BPCO sont susceptibles d’effets sur les VAD : bronchodilatateurs, corticosteroides, voire mucomodificateurs et antibiotiques. Ces effets sont pourtant mal connus. Perspectives De nouveaux traitements ciblant plus specifiquement les mecanismes de l’inflammation, du stress oxydant et du remodelage en cause dans la BPCO pourraient s’averer utiles dans sa prise en charge, mais la plupart sont encore aux stades initiaux de leur developpement. Des progres peuvent aussi venir de l’amelioration des dispositifs d’inhalation, diriges plus particulierement vers les VAD. Conclusions L’amelioration de la prise en charge de la BPCO peut passer par des progres en termes de molecules comme de mode d’administration.

2D quantitative structure–activity relationships (2D QSAR) and hologram quantitative structure–activity relationship (HQSAR) studies were performed on a series of polysubstituted quinoline derivatives as inhibitors of phosphodiesterase 4 (PDE4). The dataset was divided into training set and test set by K-means clustering. 2D QSAR study was carried out using stepwise linear regression analysis, replacement method and enhanced replacement method. Statistically significant equations with high correlation coefficient (R 2 = 0.817) and low standard deviation (SD = 0.272) were obtained. The robustness of the models was confirmed with the help of leave one out cross validation (R cv 2 = 0.740), Y scrambling (R 2 = 0.374), and by predicting the activities of test molecules (R pred 2 = 0.627). A good correlation of topology, steric and polar features of polysubstituted quinoline derivatives with the PDE4 inhibitory activity was achieved. HQSAR calculations were carried out using various combinations of fragment size, hologram length and fragment type. The best HQSAR model was obtained with an R 2 value of 0.952 and $$ R_{\text{cv}}^{2} $$ value of 0.783. The test-set of molecules was predicted by the HQSAR model. The results of 2D QSAR and HQSAR studies were used to design new molecules and to predict their activity using the developed models.

Phosphodiesterase-4 (PDE 4) enzyme has emerged as an invaluable target for the treatment of asthma, chronic obstructive pulmonary disease and rheumatoid arthritis. These findings have generated widespread interest in PDE-4 inhibitors as a potential molecular target for the development of new anti-inflammatory drugs. A series of N-substituted cis-tetra- and cis-hexahydrophthalazinone derivatives have been reported as novel, selective PDE-4 inhibitors with potent anti-inflammatory activity. In order to gain further insights into the structural requirements of novel series of N-substituted cis-tetra and cis-hexahydrophthalazinone derivatives as PDE-4 inhibitors, a three-dimensional quantitative structure activity relationship (3D-QSAR) was performed using Genetic Function Approximation (GFA). The QSAR model was generated using a training set of 45 molecules and the predictive ability of the resulting each model was assessed using a test set of 9 molecules. The internal and external consistency of final QSAR model was 0.675 and 0.750 respectively. Analysis of results from the present QSAR study indicates that shape and structural descriptors strongly govern the PDE-4 enzyme inhibitory activity. This QSAR study highlights the structural features required for PDE-4 enzyme inhibition and may be useful for design of potent PDE-4 inhibitors.

Roflumilast is a new drug with innovative pharmacodynamic properties for use in patients with chronic obstructive pulmonary disease (COPD). By selective inhibition of phosphodiesterase-4 roflumilast targets inflammatory processes in COPD, with beneficial effects on smoking-induced bronchial inflammation, fibrotic remodeling, mucociliary malfunction and oxidative stress.

BACKGROUND AND PURPOSE Platelet-derived growth factor (PDGF) modulates the airway smooth muscle (ASM) 'contractile' phenotype to a more 'proliferative' phenotype, resulting in increased proliferation and reduced contractility. Such phenotypic modulation may contribute to airway remodelling in asthma. We have previously shown that the cAMP effector molecules, protein kinase A (PKA) and the exchange protein directly activated by cAMP (Epac) inhibited PDGF-induced phenotypic modulation in bovine ASM. Here, we investigated these mechanisms in human ASM strips and cells. EXPERIMENTAL APPROACH ASM strips were incubated with PDGF in the absence or presence of the activators of Epac (8-pCPT-2'-O-Me-cAMP) or of PKA (6-Bnz-cAMP) for 4 days. Strips were mounted for isometric contraction experiments or analysed for the expression of contractile markers. Cell proliferation was measured and proliferative markers were analysed under similar conditions. KEY RESULTS Activation of Epac and PKA prevented PDGF-induced ASM strip hypocontractility, and restored the expression of smooth muscle actin, myosin and calponin, which had been markedly diminished by PDGF. Epac and PKA activation inhibited the PDGF-induced ASM cell proliferation and G1/S phase transition and the expression and phosphorylation of cell cycle regulators. CONCLUSIONS AND IMPLICATIONS Epac and PKA maintain a normally contractile ASM phenotype in a mitogenic environment, suggesting that specific activators of Epac and PKA may be beneficial in the treatment of airway remodelling in asthma.

A novel series of potential phosphodiesterase-4 (PDE-4) inhibitors, 6-(3-(cyclopentyloxy)-4-methoxyphenyl)-3-aryl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines, were developed. Different concentrations of the synthesized compounds were tested on cultured NIH-3T3 cells to determine their safety and efficacy in NIH-3T3 mouse fibroblastic cells in comparison with rolipram, a selective PDE-4 inhibitor. The viability of cells was determined by (3-(4,5-dimethylthiazol-2-yl)-2,5-di-phenyltetrazoliumbromide (MTT) assay. The PDE inhibition rate was measured indirectly by determination of concentrations of extracellular cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) using enzyme-linked immunoassay technique. The results showed that all tested compounds caused a marked increase in the concentration of cAMP, whereas the concentration of cGMP stayed approximately unchanged. The cytotoxic IC(50) of all synthesized compounds was approximately twofold greater than their required concentration for inhibition of PDE-4 (in terms of elevation of cAMP), and thus, these structures could be used to develop potent and safe inhibitors of PDE-4 enzyme.

Approximately three million people in the UK suffer from chronic obstructive pulmonary disease (COPD). Conventional therapies alleviate symptoms, improve lung function, reduce the risk of exacerbations and enhance quality of life, but COPD still commonly causes considerable morbidity and mortality. Roflumilast (Daxas®) is a recently launched maintenance treatment for adults with severe COPD associated with chronic bronchitis and frequent exacerbations. Roflumilast inhibits phosphodiesterase 4 (PDE4), a second messenger that downregulates many of the inflammatory cells contributing to COPD. In a year-long study that enrolled COPD patients with severe airflow limitation, bronchitic symptoms and a history of exacerbations, roflumilast (500 µg once daily) increased pre- and post-bronchodilator FEV1 and FVC, while reducing the number of, and increasing the time until, moderate or severe exacerbations. Nurses should remind patients that the full effects of roflumilast might take several weeks to emerge, and stress the importance of complying with treatment, even if the benefits are not immediately apparent. Common adverse events with roflumilast include diarrhoea, weight loss, nausea, abdominal pain and headache. While future studies need to resolve several outstanding issues, roflumilast seems to be an important new drug for adults with severe COPD associated with chronic bronchitis and frequent exacerbations.

We describe here the synthesis of [14C]-2-(3-chlorophenyloxy)-3-[3-(3-hydroxy)pyridin-4-yl propoxy]pyridine (1), a phosphodiesterase 4 inhibitor. [14C]-Labeled 1 was prepared in three steps from [14C]-2-bromopyridin-3-ol in an overall yield of 32%. Preparation of [14C]-labeled 2 and 3, two metabolites of 1, is also described. Copyright © 2014 John Wiley & Sons, Ltd.

Two new brominated compounds, subereaphenol K (2) and 2-(3,5-dibromo-1-ethoxy-4-oxocyclohexa-2,5-dien-1-yl)acetamide (3), together with subereaphenol B (methyl 2-(2,4-dibromo-3,6-dihydroxyphenyl)acetate; 1) with a revised structure, and five dibromotyrosine-derived metabolites, 4-8, were isolated from the sponge Suberea sp. and characterized by 1D- and 2D-NMR spectroscopic and HR-MS spectrometric data. Compounds 1, 2, 6, and 8 exhibited various weak or moderate bioactivities, including antimicrobial and cytotoxic activities. Furthermore, compounds 1 and 2 inhibited human recombinant phosphodiesterase 4 (PDE4) with IC₅₀ values of 2 μM, whereas compounds 6 and 8 were less active.

Within the wide range of nitrogen-containing heterocyclic compounds, the derivatives of 1,8-naphthyridine (NPTR) have gained a rising interest due to their reported versatile biological activities. The derivatives of NPTR scaffold are found to invite special interest from researchers nowadays on the significance of their manifestations of multiple attractive pharmacological activities which establish them as an effective and versatile tool in pharmaceutical chemistry and drug discovery. The diverse biological activities mainly include anti-inflammatory, antimicrobial, antiviral, anticancer, antihypertensive and analgesic activities. Novel NPTR scaffold has emerged its potency to treat neurological diseases like depression and Alzheimer's disease. Further these agents possess different inhibitory activities, such as anti-HIV, anti-osteoporotic, αvβ3 antagonism, antimalarial, platelet aggregation, anti-oxidant, anti-allergic, gastric antisecretory, anticonvulsant, epidermal growth factor receptor (EGFR) inhibition, protein kinase inhibition, ionotropic properties, β3 antagonism, phosphodiesterase 4 (PDE 4) inhibitions, adenosine receptor agonistic activity, adrenoceptors antagonism and DNA stabilizing activity, etc. In this review, we highlight the updates of different 1,8-naphthyridine derivatives and explain the key data available in the context of various biological activities of NPTR derivatives available from the literature. This may direct opportunity in researches in the synthesis of novel medicinal agents and the development of new heterocycles for modification of existing biological actions as well as evaluation of other possible pharmacological activities.

Multiple pharmacophore models were constructed based on the 18 crystal structures of phosphodiesterase 4 (PDE4) in complex with different inhibitors for discovering new potential PDE4 inhibitors. After validation of their efficiency in screening, 10 of the pharmacophore models were confirmed effective. Remarkably, the hits retrieved by these effective pharmacophore models were different, demonstrating that different pharmacophore models may have different performances in database screening. Therefore, all these models were employed to screen the compound database SPECS for finding potent leads with much structural diversity. Combining all the screened hits based on the 10 pharmacophore models, followed by molecular docking and bioassay, 4 of 53 tested compounds were found as active as rolipram (a well studied PDE4 inhibitor). More impressively, the four potent inhibitors with different chemical scaffolds were discovered by three different pharmacophore models separately, suggesting that a single pharmacophore model-based screening might not be efficient in thoroughly identifying potential hits from a compound database. This study also revealed that ligand-receptor complex structure-based pharmacophore is more efficient for identifying potent hits with great structural diversity in comparison with ligand-based pharmacophore and similarity search approaches. Therefore, multiple pharmacophore model-based virtual screenings should be used, if available, in combination with molecular docking for fully discovering hit compounds from compound databases.

新規医薬品の開発には多くの費用と時間を要するため、その効率化が強く望まれており、そのための有力な方法のひとつが、コンピュータと情報化学を利用して医薬品開発を行うインシリコ創薬である。特に、創薬プロセスの初期段階であるリード探索は、創薬プロセス全体の効率に大きな影響を与えるため、バーチャルスクリーニングによって質の高いリード化合物候補を発見する試みが数多く行われている。バーチャルスクリーニングを行うためのひとつの方法は、既知のリガンドからファーマコフォアモデルを構築し、それをもとにバーチャルライブラリの探索を行うことである。タンパクの立体構造を必要とせず、リガンドのみの情報で解析が可能であるという利点を持っている。ファーマコフォアモデルに基づくバーチャルスクリーニングにおいては、いかにして妥当なファーマコフォアを設定するかが重要であり、これまで様々な手法が提案されているが、決定的な手法は確立されていないのが現状である。そこで我々は、Hopfieldニューラルネットワークを利用して分子構造の重ね合わせを行うことによってファーマコフォアモデルを構築する手法を提案した。そして、その有用性を検証するため、Phosphodiesterase-4（PDE4）の阻害剤についてファーマコフォアモデルの構築を行った。活性を持つことがすでに知られている6つの阻害剤について配座探索を行い、得られた複数の配座のすべての組み合わせについて構造の重ね合わせを行った。そして、その重なりの度合いを指標として活性配座の推定を行い、ファーマコフォアを決定した。得られたファーマコフォアについて、PDE4のX線結晶構造を用いた検証を行った結果、活性部位の構造特徴を的確にとらえた妥当なモデルであることが確認された。

β-Adrenoceptor activation increases intracellular cAMP levels and consequently induces exocytotic amylase release in parotid acinar cells. Phosphodiesterase (PDE) catalyses the hydrolysis of cAMP, which terminates the downstream signaling of this second messenger. We investigated the involvement of PDE4, a cAMP-PDE, in β-adrenoceptor agonist-induced amylase release in mouse, rat and rabbit parotid acinar cells by using the specific PDE4 inhibitor rolipram. cAMP-PDE activity was detected in mouse, rat and rabbit parotid acinar cells. In the presence of rolipram, cAMP-PDE activity was reduced by about 31%, 38% and 33% in mouse, rat and rabbit parotid acinar cells, respectively. The increase in cAMP levels induced by the β-adrenoceptor agonist isoproterenol was enhanced in the presence of rolipram in mouse, rat and rabbit parotid acinar cells. Isoproterenol-induced amylase release, but not constitutive amylase release, was also enhanced in the presence of rolipram in mouse, rat and rabbit parotid acinar cells. These results suggest that the rolipram-sensitive cAMP-PDE, PDE4, is involved in β-adrenoceptor agonist-induced amylase release in parotid acinar cells. (J Oral Sci 51, 173-179, 2009)

We describe the application of a new QSAR (quantitative structure-activity relationship) formalism to the analysis and modeling of PDE-4 inhibitors. This new method takes advantage of the X-ray structural information of the PDE-4 enzyme to characterize the small molecule inhibitors. It calculates molecular descriptors based on the matching of their pharmacophore feature pairs with those (the reference) of the target binding pocket. Since the reference is derived from the X-ray crystal structures of the target under study, these descriptors are target-specific and easy to interpret. We have analyzed 35 indole derivative-based PDE-4 inhibitors where Partial Least Square (PLS) analysis has been employed to obtain the predictive models. Compared to traditional QSAR methods such as CoMFA and CoMSIA, our models are more robust and predictive measured by statistics for both the training and test sets of molecules. Our method can also identify critical pharmacophore features that are responsible for the inhibitory potency of the small molecules. Thus, this structure-based QSAR method affords both descriptive and predictive models for phosphodiesterase-4 inhibitors. The success of this study has also laid a solid foundation for systematic QSAR modeling of the PDE family of enzymes, which will ultimately contribute to chemical genomics research and drug discovery targeting the PDE enzymes.

This application claims dihydropyrazolodiazepinones as phospho-diesterase 4(PDE4) inhibitors for the treatment of asthma and chronic obstructive pulmonary disease. The compounds are shown to be potent inhibitors of PDE4B2, but no other biological data are provided. Thus, it is not clear whether these compounds provide any advantage over previously described PDE4 inhibitors or whether the issues frequently associated with PDE4 inhibitors have been addressed.

Phosphodiesterase-4 (PDE4) plays an important role in treatment of asthma and chronic obstructive pulmonary disease. Thirty-one analogs displaying variable inhibition of PDE4 were selected to develop models for establishing three-dimensional quantitative structure-activity relationships (3D-QSAR). Comparative molecular field analysis (CoMFA) was conducted on the group of analogs to determine the structural requirements for potency in inhibiting PDE4. The resulting model exhibited good q2 and r2 values up to 0.741 and 0.954 for CoMFA. The contributions from the steric and electrostatic fields were 0.915 and 0.085 respectively. The 3D-QSAR model should be very useful for design of novel PDE 4 inhibitors.

Psoriasis is a common, chronic and disabling skin disorder affecting approximately 2% of the population, associated with significant negative impact on the patient's quality of life. Approximately 80% of those affected with psoriasis have mild-to-moderate forms and are usually treated with topical therapy, whereas phototherapy and systemic therapies are used for those with severe disease. In the past three decades, the major advances in psoriasis therapy have been in systemic agents for the treatment of moderate-to-severe psoriasis, particularly new immunomodulatory and biological molecules, while topical therapies have remained relatively unchanged over the past decades. Indeed, topical corticosteroids and vitamin D3 analogs are still the gold standard of therapy for mild-to-moderate psoriasis. Thus, there is a need to develop new and more effective topical agents in the short and long term, with a better efficacy and safety profile than corticosteroids and vitamin D3 analogs. Over the past five years, investigation into topical therapy has expanded, with exciting new drugs being developed. Preliminary results of these emerging agents that selectively target disease-defining pathogenic pathways seem to be promising, although long-term and large-scale studies assessing safety and efficacy are still lacking. The aim of this article was to review the clinical and research data of some emerging topical agents, focusing on Janus kinase-signal transducer and activator of transcription and phosphodiesterase type 4 inhibitors, which are currently being investigated.

Objective: Recent evidence suggests an important role for cAMP-dependent pathways in modulation of innate immune function. Phosphodiesterase 4 (PDE4) is widely expressed in innate immune cells such as macrophages/dendritic cells with potent anti-inflammatory effects on pharmacologic inhibition of the enzyme. We investigated the importance of PDE4 in diet-induced obesity (DIO) and hypothesized that PDE4 inhibition will improve insulin sensitivity and reduce inflammation. Methods and Results: PDE4 was upregulated in both visceral and subcutaneous (SubQ) white adipose tissue (WAT) in DIO mice (12 weeks of high-fat diet, HFD, 60% fat) compared to normal-chow diet (NCD) mice (↑4∼10-folds, p+ F4/80 + cells, r=0.56, p50 0.39 nM) versus vehicle control (n=6∼10 in each group) for 21 days concomitant with HFD, resulted in rapid and substantial weight loss (↓45.8% fat content), enhanced thermogenesis [(∼20% higher oxygen consumption and heat production, 0.7∼1.1°C higher core body temperature in a cold environment (4°C)], brown adipose reprogramming, improvement in insulin resistance (HOMA-IR ↓ from 0.69±0.04 to 0.44±0.01, pIn-vitro treatment of mouse bone marrow-derived macrophages (BMDM) promoted Altf and increased expression of tyrosine hydroxylase (↑2.5 folds) and catecholamines secretion. Additional experiments with agents that augment/reduce intracellular cAMP/EPAC/AMPK revealed an essential role for this cascade in Altf activation and catecholamine release. Conclusions: PDE4 antagonism improves obese diabetic symptoms through convergent pathways involving Altf activation and enhancing thermogenesis via cAMP dependent modulation of macrophage catecholamine release.

Phosphodiesterase-4 (PDE4) and neuroimmune signaling have been posited to regulate alcohol drinking.This study evaluated the involvement of PDE4 and Il22ra2 on ethanol (EtOH) intake by alcohol-preferring (P) and high-alcohol-drinking (HAD1) rats.Exp 1 determined the dose-response effects of PDE4 inhibitors, rolipram, and Ro 20-1724, on 2 h/day free-choice EtOH intake by adult P and HAD1 rats. Exps 2-3 examined the effects of repeated administration with the PDE4 inhibitors on EtOH or sucrose intake and locomotor behavior. Exp 4 determined Pde4-associated gene expression differences in subregions of the extended amygdala, between high- and low-alcohol-consuming rat lines. Exp 5 evaluated the effects of infusing short hairpin RNA to knock down Il22ra2 in the nucleus accumbens (NAc) shell on a 24-h free-choice EtOH drinking by P rats.Administration of rolipram or Ro 20-1724 reduced EtOH intake by P rats; Ro 20-1724 reduced EtOH intake by HAD1 rats. Repeated rolipram or Ro 20-1724 exposure reduced EtOH intake by P and HAD1 rats. PDE4 inhibition induced motor impairment during the first hour of EtOH intake by P rats. Higher gene expression levels for PDE4A were found in the NAc shell of P vs NP rats. ShRNAs targeting Il22ra2 in the NAc shell significantly reduced chronic EtOH intake.PDE4 and neuroinflammatory/immune signaling pathways could represent molecular targets for the treatment of alcohol use disorders in genetically predisposed subjects. This study underscores the importance of testing compounds over multiple days and rat lines when determining efficacy to disrupt excessive alcohol intake.

Psoriasis is a chronic immune-mediated inflammatory condition that affects 2-3% of the population. Apremilast was FDA-approved in March 2014 for the treatment of psoriatic arthritis and in September 2014 for the treatment of moderate to severe plaque psoriasis. Apremilast appears to have lower efficacy than some biologic agents such as adalimumab and ustekinumab, which achieve a PASI-75 in approximately 70% of patients after 12-16 weeks of therapy. However, its ease of administration as an oral agent coupled with a mild side effect profile make it an attractive option for psoriasis treatment. Herein, we present a patient with a 17-year history of plaque type psoriasis recalcitrant to topical, oral, and biologic mediations who attained near-complete remission after therapy with a combination of adalimumab and apremilast.

Intracellular cyclic AMP regulation systems play an important role in the mechanisms of morphine dependence and withdrawal. In the present study, to clarify the involvement of phosphodiesterase (PDE) 4, degradation enzyme of cyclic AMP in morphine dependence and withdrawal we investigated the activities of PDE4 after naloxone-precipitation in single morphine treatment and repeated morphine treatment (morphine-dependence) rats. Naloxone (5 mg/kg, s.c.) challenge caused a significant withdrawal signs such as jumping in morphine-dependent rats following repeated treatment with morphine (4, 8, 12, and 16 mg/kg, twice a day for 4 days), but not in single morphine-treated rats (16 mg/kg, single). Naloxone challenge caused an increase in PDE4 activities in the brain of rats treated with single morphine in connection with the elevation of brain cyclic AMP. In contrast, increase in the PDE4 activities was not caused by naloxone challenge in all brain regions of morphine-dependent rats, although brain cyclic AMP was significantly increased. These results suggest that the lack of PDE4 activation leading to remarkable elevation of cyclic AMP is involved in naloxone-precipitated morphine withdrawal symptoms.

Asthma is a very common condition that can be managed well pharmacologically. In contrast, the presently available management of chronic obstructive pulmonary disease (COPD) is poor. The phosphodiesterase 4 inhibitor roflumilast has an anti-inflammatory effect, and has recently been shown to reduce the early and late responses in mild allergic asthma. Roflumilast may become a steroid-free option for those patients who do not tolerate or want to take long-term corticosteroids to prevent asthma. In COPD, roflumilast improved measures of pulmonary function, quality of life and well being. As the inflammation of COPD is resistant to corticosteroids, roflumilast has potential as an anti-inflammatory agent in the treatment of COPD. Roflumilast is generally well tolerated.

Based on our results regarding the structure-activity relationships of alkylxanthines and imidazo[2,1-i]purines as phosphodiesterase 4 (PDE4) inhibitors, we designed new 1-benzylxanthines and investigated their PDE4 inhibitory activities. 3,7-Dihydro-7-acetonyl-1-(2,4-dichlorobenzyl)-3-propyl-1H-purine-2,4-dione (2h) exhibited both more selective and more potent PDE4 inhibitory activity than rolipram and XT-611.

Objective: Phosphodiesterase 4 (PDE4) catabolizes the second messenger 3′, 5′-cyclic adenosine monophosphate and may play a critical role in brain diseases. Our aim was to quantify PDE4 in rats with positron emission tomography (PET). Methods: High (n = 6) and low specific activity (SA) (n = 2) higher affinity ((R)-[11C]rolipram) and high SA lower affinity ((S)-[11C]rolipram) (n = 2) enantiomers were intravenously administered to Sprague–Dawley rats. Brain data were acquired using the ATLAS PET scanner and reconstructed using the 3D-ordered subset expectation maximization algorithm. Arterial samples were taken to measure unmetabolized [11C]rolipram. Total distribution volumes (VT′) were calculated using a 1-tissue compartment (1C) and an unconstrained 2-tissue compartment (2C) model. Results: High SA R experiments showed later and greater brain uptake, and slower washout than low SA R and S experiments. In all regions and in all experiments, the 2C model gave significantly better fitting than the 1C model. The poor fitting by the latter caused underestimation of VT′ by 19–31%. The 2C model identified VT′ reasonably well with coefficients of variation less than 10%. VT′ values by this model were 16.4–29.2 mL/cm3 in high SA R, 2.9–3.5 in low SA R, and 3.1–3.7 in S experiments. Conclusions: Specific binding of (R)-[11C]rolipram was accurately measured in living rats. In high SA R experiments, ∼86% of VT′ was specific binding. Distribution and changes of PDE4 in animal models can now be studied by measuring VT′ of high SA (R)-[11C]rolipram.

Purpose of review Chronic obstructive pulmonary disease (COPD) is a disease state characterized by airflow limitation that is usually progressive. In addition, an abnormal inflammatory response of the lungs to noxious particles or gases can be seen throughout the airways, parenchyma, and pulmonary vasculature. So far, anti-inflammatory medications (eg, inhaled corticosteroids) have failed to show a major effect on the decline of lung function in COPD patients. Novel anti-inflammatory therapies such as selective phosphodiesterase 4 (PDE4) inhibitors are in clinical development. Their potential role in the management of COPD is described in this review. Recent findings Some of the selective PDE4 inhibitors have demonstrated in vitro and in vivo anti-inflammatory activity on cells commonly linked to airway inflammation in COPD, such as neutrophils. While these agents seem to offer only a modest improvement in lung function compared with other bronchodilators, their anti-inflammatory effects appear to provide some substantial benefits in reducing exacerbations and improving health-related quality of life. Summary Based on the available data, the second generation of selective PDE4 inhibitors will likely provide additional therapeutic options for the management of COPD. These agents may become an important tool in the treatment of this disease, since they target three important components of COPD: airway obstruction, inflammation, and structural changes.

A rapid, versatile and one-pot Cu-mediated domino reaction has been developed for facile assembly of two six membered fused N-heterocyclic rings leading to novel small molecules as potential inhibitors of PDE4.

We investigated the structure-activity relationship of the (R)- and (S)-isomer of 7-methyl- and 8-alkyl-tetrahydroimidazo[2,1-i]purines for phosphodiesterase 4 (PDE4) inhibitors. (S)-8-Isopropyl-3,4-dipropyl-imizazo[2,1-i]purine (S)-2c exhibited both potent and selective PDE4 inhibitory activity.