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https://www.readbyqxmd.com/read/27901486/triple-negative-breast-cancer-development-can-be-selectively-suppressed-by-sustaining-an-elevated-level-of-cellular-cyclic-amp-through-simultaneously-blocking-its-efflux-and-decomposition
#1
Wei Wang, Yue Li, Jessica Y Zhu, Dongdong Fang, Han-Fei Ding, Zheng Dong, Qing Jing, Shi-Bing Su, Shuang Huang
Triple negative breast cancer (TNBC) has the highest mortality among all breast cancer types and lack of targeted therapy is a key factor contributing to its high mortality rate. In this study, we show that 8-bromo-cAMP, a cyclic adenosine monophosphate (cAMP) analog at high concentration (> 1 mM) selectively suppresses TNBC cell growth. However, commonly-used cAMP-elevating agents such as adenylyl cyclase activator forskolin and pan phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) are ineffective...
November 25, 2016: Oncotarget
https://www.readbyqxmd.com/read/27890378/design-and-synthesis-of-4-5-6-7-tetrahydro-1h-1-2-diazepin-7-one-derivatives-as-a-new-series-of-phosphodiesterase-4-pde4-inhibitors
#2
Sara Guariento, Anna Karawajczyk, James A Bull, Gessica Marchini, Martyna Bielska, Xenia Iwanowa, Olga Bruno, Paola Fossa, Fabrizio Giordanetto
Phosphodiesterase 4 (PDE4) inhibitors have attractive therapeutic potential in respiratory, inflammatory, metabolic and CNS disorders. The present work details the design, chemical exploration and biological profile of a novel PDE4 inhibitor chemotype. A diazepinone ring was identified as an under-represented heterocyclic system fulfilling a set of PDE4 structure-based design hypotheses. Rapid exploration of the structure activity relationships for the series was enabled by robust and scalable two/three-steps parallel chemistry protocols...
November 16, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27878061/oral-apremilast-for-the-treatment-of-plaque-psoriasis
#3
REVIEW
James Q Del Rosso, Leon Kircik
This article provides an update on the use of oral apremilast, a phosphodiesterase-4 (PDE4) inhibitor, for the treatment of plaque psoriasis. Emphasis is placed on safety evaluations, although efficacy considerations are also addressed. Both two-year and three -year data analyses support the favorable safety profile reported in pivotal trials with this agent. Although effective in many study subjects despite baseline characteristics, higher response rates were noted in those with a baseline psoriasis area and severity index (PASI) score <20 and in subjects not previously treated with systemic therapy for psoriasis...
September 2016: Journal of Clinical and Aesthetic Dermatology
https://www.readbyqxmd.com/read/27869356/apremilast-an-oral-phosphodiesterase-4-pde4-inhibitor-a-novel-treatment-option-for-nurse-practitioners-treating-patients-with-psoriatic-disease
#4
Melodie Young, Heather L Roebuck
BACKGROUND AND PURPOSE: Apremilast is an oral nonbiologic medication approved for the treatment of adult patients with active psoriatic arthritis and for patients with moderate to severe plaque psoriasis. This article summarizes the efficacy and safety of apremilast and provides characterization of the novel medication with clinical perspectives to successfully incorporate this therapy into practice for appropriate patients. DATA SOURCES: A review and synthesis of the results from the ESTEEM (Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis) phase 3 clinical studies evaluating the efficacy, safety, and tolerability of apremilast for the treatment of moderate to severe plaque psoriasis was conducted...
December 2016: Journal of the American Association of Nurse Practitioners
https://www.readbyqxmd.com/read/27859531/increase-of-intracellular-cyclic-amp-by-pde4-inhibitors-affects-hepg2-cell-cycle-progression-and-survival
#5
Mara Massimi, Silvia Cardarelli, Francesca Galli, Maria Federica Giardi, Federica Ragusa, Nadia Panera, Benedetta Cinque, Maria Grazia Cifone, Stefano Biagioni, Mauro Giorgi
Type 4 cyclic nucleotide phosphodiesterases (PDE4) are major members of a superfamily of enzymes (PDE) involved in modulation of intracellular signaling mediated by cAMP. Broadly expressed in most human tissues and present in large amounts in the liver, PDEs have in the last decade been key therapeutic targets for several inflammatory diseases. Recently, a significant body of work has underscored their involvement in different kinds of cancer, but with no attention paid to liver cancer. The present study investigated the effects of two PDE4 inhibitors, rolipram and DC-TA-46, on the growth of human hepatoma HepG2 cells...
November 16, 2016: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/27844172/xanthines-and-phosphodiesterase-inhibitors
#6
D Spina, C P Page
Theophylline is an orally acting xanthine that has been used since 1937 for the treatment of respiratory diseases including asthma and chronic obstructive pulmonary disease (COPD). However, in most treatment guidelines, xanthines have now been consigned to third-line therapy because of their narrow therapeutic window and propensity for drug-drug interactions. However, lower than conventional doses of theophylline considered to be bronchodilator are now known to have anti-inflammatory actions of relevance to the treatment of respiratory disease...
November 15, 2016: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/27843073/off-target-effect-of-sildenafil-on-postsurgical-erectile-dysfunction-alternate-pathways-and-localized-delivery-system
#7
Amirali Salmasi, Geun Taek Lee, Neal Patel, Ritu Goyal, Michael Dinizo, Young Suk Kwon, Part K Modi, Izak Faiena, Nara Lee, Johanna L Hannan, Joachim Kohn, Isaac Yi Kim
INTRODUCTION: There is no consensus on the best oral phosphodiesterase type 5 inhibitor (PDE5I) for patients undergoing penile rehabilitation after surgical nerve injury. AIM: To determine the mechanism of PDE5I on cultured neuronal cells and the effectiveness of local drug delivery using nanospheres (NSPs) to sites of nerve injury in a rat model of bilateral cavernous nerve injury (BCNI). METHODS: The effects of sildenafil, tadalafil, and vardenafil on cyclic adenosine monophosphate, cyclic guanosine monophosphate, and cell survival after exposure to hypoxia and H2O2 were measured in PC12, SH-SY5Y, and NTERA-2 (NT2) cell cultures...
November 11, 2016: Journal of Sexual Medicine
https://www.readbyqxmd.com/read/27836756/cyclic-nucleotide-phosphodiesterases-in-human-spermatozoa-and-seminal-fluid-presence-of-an-active-pde10a-in-human-spermatozoa
#8
Loïze Maréchal, Christine Guillemette, Serge Goupil, Patrick Blondin, Pierre Leclerc, François J Richard
BACKGROUND: Cyclic adenosine monophosphate (cAMP) plays a crucial role as a signaling molecule for sperm functions such as capacitation, motility and acrosome reaction. It is well known that cAMP degradation by phosphodiesterase (PDE) enzyme has a major impact on sperm functions. The present study was undertaken to characterize cAMP-PDE activity in human semen. METHODS: cAMP-PDE activity was measured in human sperm and seminal plasma using family specific PDE inhibitors...
November 9, 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27813474/-cyclic-nucleotide-phosphodiesterases-role-in-the-heart-and-therapeutic-perspectives
#9
Ibrahim Bedioune, Pierre Bobin, Sarah Karam, Marta Lindner, Delphine Mika, Patrick Lechêne, Jérôme Leroy, Rodolphe Fischmeister, Grégoire Vandecasteele
Cyclic nucleotide phosphodiesterases (PDEs) degrade the second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), thereby regulating multiple aspects of cardiac function. This highly diverse class of enzymes encoded by 21 genes encompasses 11 families that are not only responsible for the termination of cyclic nucleotide signalling, but are also involved in the generation of dynamic microdomains of cAMP and cGMP, controlling specific cell functions in response to various neurohormonal stimuli...
2016: Biologie Aujourd'hui
https://www.readbyqxmd.com/read/27804148/efficacy-of-phosphodiesterase-4-inhibitors-in-juvenile-batten-disease-cln3
#10
Amy Aldrich, Megan E Bosch, Rachel Fallet, Jessica Odvody, Maria Burkovetskaya, Kakulavarapu V Rama Rao, Jonathan D Cooper, Arlene V Drack, Tammy Kielian
OBJECTIVE: Juvenile Neuronal Ceroid Lipofuscinosis (JNCL), or juvenile Batten disease, is a pediatric lysosomal storage disease caused by autosomal recessive mutations in CLN3, typified by blindness, seizures, progressive cognitive and motor decline, and premature death. Currently, there is no treatment for JNCL that slows disease progression, which highlights the need to explore novel strategies to extend the survival and quality-of-life of afflicted children. Cyclic AMP (cAMP) is a second messenger with pleiotropic effects, including regulating neuroinflammation and neuronal survival...
November 2, 2016: Annals of Neurology
https://www.readbyqxmd.com/read/27756749/phosphodiesterase-4-inhibitors-have-wide-ranging-activity-in-b-cell-malignancies
#11
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
https://www.readbyqxmd.com/read/27732797/nanodomain-regulation-of-cardiac-cyclic-nucleotide-signaling-by-phosphodiesterases
#12
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
https://www.readbyqxmd.com/read/27731313/targeted-delivery-of-an-anti-inflammatory-pde4-inhibitor-to-immune-cells-via-an-antibody-drug-conjugate
#13
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
https://www.readbyqxmd.com/read/27725657/camp-signaling-in-brain-is-decreased-in-unmedicated-depressed-patients-and-increased-by-treatment-with-a-selective-serotonin-reuptake-inhibitor
#14
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
https://www.readbyqxmd.com/read/27695125/synthesis-pharmacological-profile-and-docking-studies-of-new-sulfonamides-designed-as-phosphodiesterase-4-inhibitors
#15
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
https://www.readbyqxmd.com/read/27690383/discovery-of-n-alkyl-catecholamides-as-selective-phosphodiesterase-4-inhibitors-with-anti-neuroinflammation-potential-exhibiting-antidepressant-like-effects-at-non-emetic-doses
#16
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
https://www.readbyqxmd.com/read/27685753/inhibition-of-phosphodiesterase-3-4-and-5-induces-endolymphatic-hydrops-in-mouse-inner-ear-as-evaluated-with-repeated-9-4t-mri
#17
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
https://www.readbyqxmd.com/read/27665850/ferulic-acid-prevents-lps-induced-up-regulation-of-pde4b-and-stimulates-the-camp-creb-signaling-pathway-in-pc12-cells
#18
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...
December 2016: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/27664396/-18f-jnj42259152-binding-to-phosphodiesterase-pde10a-a-key-regulator-of-medium-spiny-neuron-excitability-is-altered-in-the-presence-of-cyclic-amp
#19
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
https://www.readbyqxmd.com/read/27608741/structure-based-design-of-selective-phosphodiesterase-4b-inhibitors-based-on-ginger-phenolic-compounds
#20
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
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