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pde4 inhibitor

Jeffrey D Cooney, Ricardo C T Aguiar
Phosphodiesterase 4 (PDE4) inhibition restores the suppressive effects of cyclic-AMP in lymphocytes. In this concise review, we detail how PDE4 inhibition downmodulates the B-cell receptor (BCR)-related kinases SYK and PI3K, inhibits VEGFA secretion by tumor cells, inducing cancer cell apoptosis and blocking angiogenesis in the microenvironment. We describe the successful clinical repurposing of PDE4 inhibitors in B-cell malignancies, and propose that given their anti-inflammatory/immunomodulatory activity, these agents will suppress BCR signals without the toxicity associated with other targeted biological doublets...
October 18, 2016: Blood
Kristen Kokkonen, David A Kass
Cyclic nucleotide phosphodiesterases (PDEs) form an 11-member superfamily comprising 100 different isoforms that regulate the second messengers cyclic adenosine or guanosine 3',5'-monophosphate (cAMP or cGMP). These PDE isoforms differ with respect to substrate selectivity and their localized control of cAMP and cGMP within nanodomains that target specific cellular pools and synthesis pathways for the cyclic nucleotides. Seven PDE family members are physiologically relevant to regulating cardiac function, disease remodeling of the heart, or both: PDE1 and PDE2, both dual-substrate (cAMP and cGMP) esterases; PDE3, PDE4, and PDE8, which principally hydrolyze cAMP; and PDE5A and PDE9A, which target cGMP...
October 12, 2016: Annual Review of Pharmacology and Toxicology
Shan Yu, Aaron D Pearson, Reyna K V Lim, David T Rodgers, Sijia Li, Holly B Parker, Meredith Weglarz, Eric N Hampton, Michael J Bollong, Jiayin Shen, Claudio Zambaldo, Danling Wang, Ashley K Woods, Timothy M Wright, Peter G Schultz, Stephanie A Kazane, Travis S Young, Matthew S Tremblay
Phosphodiesterase 4 (PDE4) inhibitors are approved for the treatment of some moderate to severe inflammatory conditions. However, dose-limiting side effects in the central nervous system and gastrointestinal tract, including nausea, emesis, headache, and diarrhea, have impeded the broader therapeutic application of PDE4 inhibitors. We sought to exploit the wealth of validation surrounding PDE4 inhibition by improving the therapeutic index through generation of an antibody-drug conjugate (ADC) that selectively targets immune cells through the CD11a antigen...
October 12, 2016: Molecular Therapy: the Journal of the American Society of Gene Therapy
M Fujita, E M Richards, M J Niciu, D F Ionescu, S S Zoghbi, J Hong, S Telu, C S Hines, V W Pike, C A Zarate, R B Innis
Basic studies exploring the importance of the cyclic adenosine monophosphate (cAMP) cascade in major depressive disorder (MDD) have noted that the cAMP cascade is downregulated in MDD and upregulated by antidepressant treatment. We investigated cAMP cascade activity by using (11)C-(R)-rolipram to image phosphodiesterase-4 (PDE4) in unmedicated MDD patients and after ~8 weeks of treatment with a selective serotonin reuptake inhibitor (SSRI). (11)C-(R)-rolipram positron emission tomographic (PET) scans were performed in 44 unmedicated patients during a major depressive episode and 35 healthy controls...
October 11, 2016: Molecular Psychiatry
Isabelle Karine da Costa Nunes, Everton Tenório de Souza, Suzana Vanessa S Cardozo, Vinicius de Frias Carvalho, Nelilma Correia Romeiro, Patrícia Machado Rodrigues E Silva, Marco Aurélio Martins, Eliezer J Barreiro, Lídia Moreira Lima
Prior investigations showed that increased levels of cyclic AMP down-regulate lung inflammatory changes, stimulating the interest in phosphodiesterase (PDE)4 as therapeutic target. Here, we described the synthesis, pharmacological profile and docking properties of a novel sulfonamide series (5 and 6a-k) designed as PDE4 inhibitors. Compounds were screened for their selectivity against the four isoforms of human PDE4 using an IMAP fluorescence polarized protocol. The effect on allergen- or LPS-induced lung inflammation and airway hyper-reactivity (AHR) was studied in A/J mice, while the xylazine/ketamine-induced anesthesia test was employed as a behavioral correlate of emesis in rodents...
2016: PloS One
Zhong-Zhen Zhou, Yu-Fang Cheng, Zheng-Qiang Zou, Bing-Chen Ge, Hui Yu, Cang Huang, Hai-Tao Wang, Xue-Mei Yang, Jiang-Ping Xu
Depression involving neuroinflammation is one of the most common disabling and life-threatening psychiatric disorders. Phosphodiesterase 4 (PDE4) inhibitors produce potent antidepressant-like and cognition-enhancing effects. However, their clinical utility is limited by their major side effect of emesis. To obtain more selective PDE4 inhibitors with antidepressant and anti-neuroinflammation potential and less side effect of emesis, we designed and synthesized a series of N-alkyl catecholamides by modifying the 4-methoxybenzyl group of our hit compound, FCPE07, with an alkyl side chain...
October 3, 2016: ACS Chemical Neuroscience
Eva Degerman, Rene In 't Zandt, Annki Pålbrink, Lena Eliasson, Per Cayé-Thomasen, Måns Magnusson
CONCLUSION: The data indicate important roles for phosphodiesterase (PDE) 3, 4, 5, and related cAMP and cGMP pools in the regulation of inner ear fluid homeostasis. Thus, dysfunction of these enzymes might contribute to pathologies of the inner ear. OBJECTIVE: The mechanisms underlying endolymphatic hydrops, a hallmark of inner ear dysfunction, are not known in detail; however, altered balance in cAMP and cGMP signaling systems appears to be involved. Key components of these systems are PDEs, enzymes that modulate the amplitude, duration, termination, and specificity of cAMP and cGMP signaling...
August 15, 2016: Acta Oto-laryngologica
Hao Huang, Qian Hong, Hong-Ling Tan, Cheng-Rong Xiao, Yue Gao
AIM: Phosphodiesterase 4 (PDE4) isozymes are involved in different functions, depending on their patterns of distribution in the brain. The PDE4 subtypes are distributed in different inflammatory cells, and appear to be important regulators of inflammatory processes. In this study we examined the effects of ferulic acid (FA), a plant component with strong anti-oxidant and anti-inflammatory activities, on lipopolysaccharide (LPS)-induced up-regulation of phosphodiesterase 4B (PDE4B) in PC12 cells, which in turn regulated cellular cAMP levels and the cAMP/cAMP response element binding protein (CREB) pathway in the cells...
September 26, 2016: Acta Pharmacologica Sinica
Maarten Ooms, Bala Attili, Sofie Celen, Michel Koole, Alfons Verbruggen, Koen Van Laere, Guy Bormans
Phosphodiesterase 10A (PDE10A) is a key regulator of medium spiny neuron excitability. Therefore, it plays an important role in the regulation of motor, reward and cognitive processes. Despite the interest in PDE10A as a drug and PET imaging target, little is known about the regulation of PDE10A enzymatic activity. This study aimed to further investigate the role of cAMP in the regulation of PDE10A activity and PDE10A PET imaging. Using [(18) F]JNJ42259152 as radioligand, we investigated alterations in PDE10A binding secondary to changes in cAMP levels...
September 24, 2016: Journal of Neurochemistry
Ming Xing, Gabriel Akyirem Akowuah, Vertika Gautam, Anand Gaurav
Phosphodiesterase 4 (PDE4) has been established as a drug target for inflammatory diseases of respiratory tract like asthma and chronic obstructive pulmonary disease. The selective inhibitors of PDE4B, a subtype of PDE4, are devoid of adverse effect like nausea and vomiting commonly associated with non-selective PDE4B inhibitors. This makes the development of PDE4B subtype selective inhibitors a desirable research goal. Thus, in the present study, molecular docking, molecular dynamic simulations and binding free energy were performed to explore potential selective PDE4B inhibitors based on ginger phenolic compounds...
September 9, 2016: Journal of Biomolecular Structure & Dynamics
Amanda G Vang, Chaitali Basole, Hongli Dong, Rebecca K Nguyen, William Housley, Linda Guernsey, Alexander J Adami, Roger S Thrall, Robert B Clark, Paul M Epstein, Stefan Brocke
Abolishing the inhibitory signal of intracellular cAMP is a prerequisite for effector T (Teff) cell function. The regulation of cAMP within leukocytes critically depends on its degradation by cyclic nucleotide phosphodiesterases (PDEs). We have previously shown that PDE8A, a PDE isoform with 40-100-fold greater affinity for cAMP than PDE4, is selectively expressed in Teff vs. regulatory T (Treg) cells and controls CD4(+) Teff cell adhesion and chemotaxis. Here, we determined PDE8A expression and function in CD4(+) Teff cell populations in vivo...
2016: Frontiers in Pharmacology
Masami Shimizu-Albergine, Brian Van Yserloo, Martin G Golkowski, Shao-En Ong, Joseph A Beavo, Karin E Bornfeldt
Luteinizing hormone (LH) stimulates steroidogenesis largely through a surge in cyclic AMP (cAMP). Steroidogenic rates are also critically dependent on the availability of cholesterol at mitochondrial sites of synthesis. This cholesterol is provided by cellular uptake of lipoproteins, mobilization of intracellular lipid, and de novo synthesis. Whether and how these pathways are coordinated by cAMP are poorly understood. Recent phosphoproteomic analyses of cAMP-dependent phosphorylation sites in MA10 Leydig cells suggested that cAMP regulates multiple steps in these processes, including activation of the SCAP/SREBP pathway...
September 20, 2016: Proceedings of the National Academy of Sciences of the United States of America
Zhong-Zhen Zhou, Bing-Chen Ge, Qiu-Ping Zhong, Chang Huang, Yu-Fang Cheng, Xue-Mei Yang, Hai-Tao Wang, Jiang-Ping Xu
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...
August 24, 2016: European Journal of Medicinal Chemistry
Chiara Brullo, Roberta Ricciarelli, Jos Prickaerts, Ottavio Arancio, Matteo Massa, Chiara Rotolo, Alessia Romussi, Claudia Rebosio, Barbara Marengo, Maria Adelaide Pronzato, Britt T J van Hagen, Nick P van Goethem, Pasqualina D'Ursi, Alessandro Orro, Luciano Milanesi, Sara Guariento, Elena Cichero, Paola Fossa, Ernesto Fedele, Olga Bruno
Phosphodiesterase type 4D (PDE4D) has been indicated as a promising target for treating neurodegenerative pathologies such as Alzheimer's Disease (AD). By preventing cAMP hydrolysis, PDE4 inhibitors (PDE4Is) increase the cAMP response element-binding protein (CREB) phosphorylation, synaptic plasticity and long-term memory formation. Pharmacological and behavioral studies on our hit GEBR-7b demonstrated that selective PDE4DIs could improve memory without causing emesis and sedation. The hit development led to new molecule series, herein reported, characterized by a catechol structure bonded to five member heterocycles...
August 13, 2016: European Journal of Medicinal Chemistry
Pasqualina D'Ursi, Sara Guariento, Gabriele Trombetti, Alessandro Orro, Elena Cichero, Luciano Milanesi, Paola Fossa, Olga Bruno
Alzheimer's disease has recently emerged as a possible field of application for PDE4D inhibitors (PDE4DIs). The great structure similarity among the various PDE4 isoforms and, furthermore, the lack of the full length crystal structure of the enzyme, impaired the rational design of new selective PDE4DIs. In this paper, with the aim of exploring new insights into the PDE4D binding, we tackled the problem by performing a computational study based on docking simulations combined with molecular dynamics (D-MD). Our work uniquely identified the binding mode and the key residues involved in the interaction with a number of in-house catechol iminoether derivatives, acting as PDE4DIs...
September 2016: Molecular Informatics
Kevin R Kelly, Alex Mejia, Avvaru Suhasini, An-Ping Lin, John G Kuhn, Anand Karnad, Steven Weitman, Ricardo C T Aguiar
PURPOSE: In this study, we aimed to validate our extensive pre-clinical data on phosphodiesterase 4 (PDE4) as actionable target in B-cell malignancies. Our specific objectives were to determine the safety, pharmacokinetics and pharmacodynamics (PI3K/AKT activity), as well as to capture any potential anti-tumor activity of the FDA-approved PDE4 inhibitor roflumilast in combination with prednisone in patients with advanced B cell malignancies. EXPERIMENTAL DESIGN: Single center, exploratory phase Ib open-label, non-randomized study...
August 19, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Ali N Chamseddine, Monica Cabrero, Yue Wei, Irene Ganan-Gomez, Simona Colla, Koichi Takahashi, Hui Yang, Zachary S Bohannan, Guillermo Garcia-Manero
BACKGROUND (OR PURPOSE): Inflammation has an essential role in the pathogenesis of myelodysplastic syndromes (MDS). Its expression is controlled by phosphodiesterase 4 (PDE4). Thus, PDE4 inhibitors might be useful therapeutic targets for MDS. PATIENTS (OR MATERIALS) AND METHODS: We evaluated the expression of each isoform of PDE4 (A, B, C, and D) using transcriptomic profiling and examined the potential impact on the outcome of patients with MDS in terms of survival and response to hypomethylating agents...
August 2016: Clinical Lymphoma, Myeloma & Leukemia
Amy S Paller, Wynnis L Tom, Mark G Lebwohl, Robin L Blumenthal, Mark Boguniewicz, Robert S Call, Lawrence F Eichenfield, Douglass W Forsha, William C Rees, Eric L Simpson, Mary C Spellman, Linda F Stein Gold, Andrea L Zaenglein, Matilda H Hughes, Lee T Zane, Adelaide A Hebert
BACKGROUND: Additional topical treatments for atopic dermatitis (AD) are needed that provide relief while minimizing risks. OBJECTIVE: We sought to assess the efficacy and safety of crisaborole ointment, a phosphodiesterase 4 inhibitor, in two phase III AD studies (AD-301: NCT02118766; AD-302: NCT02118792). METHODS: Two identically designed, vehicle-controlled, double-blind studies enrolled and randomly assigned (2:1, crisaborole:vehicle) patients aged 2 years or older with an Investigator's Static Global Assessment (ISGA) score of mild or moderate for twice-daily application for 28 days...
September 2016: Journal of the American Academy of Dermatology
Hiroshi Koga, Andreas Recke, Gestur Vidarsson, Hendri H Pas, Marcel F Jonkman, Takashi Hashimoto, Anika Kasprick, Saeedeh Ghorbanalipoor, Hermann Tenor, Detlef Zillikens, Ralf J Ludwig
Pemphigoid diseases such as epidermolysis bullosa acquisita (EBA) may be difficult to treat. In pemphigoid diseases, mucocutaneous blistering is caused by autoantibodies to hemidesmosomal antigens; in EBA the autoantigen is type VII collagen. Despite growing insights into pemphigoid disease pathogenesis, corticosteroids are still a mainstay of treatment. In experimental EBA, myeloid cell activation is a key event leading to blistering. Activation of these cells depends on phosphodiesterase (PDE) 4. We therefore evaluated the potential for PDE4 inhibition in EBA: PDE4 was highly expressed in inflammatory cells and in the epidermis of patients compared with healthy skin samples...
July 5, 2016: Journal of Investigative Dermatology
Luca Bianchi, Ester Del Duca, Marco Romanelli, Rosita Saraceno, Sergio Chimenti, Andrea Chiricozzi
INTRODUCTION: Psoriasis is a chronic inflammatory skin disease affecting 2-3% of the population. Certain systemic drugs currently available for its treatment could be associated, in the long term, with organ toxicity and adverse events, thus, clinical monitoring throughout treatment is required. Moreover, tolerability issues, parenteral administration, and barriers to patient access, such as high cost and specialist management lead to treatment failure. AREAS COVERED: Apremilast is an oral small molecule inhibitor of phosphodiesterase 4 (PDE4i)...
September 2016: Expert Opinion on Drug Metabolism & Toxicology
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