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pde4 inhibitor

Lamei Yu, Kuichang Yuan, Byung Mun Park, Suhn Hee Kim
This study aimed to determine the effects of levosimendan, a calcium sensitizer, on atrial contractility and atrial natriuretic peptide (ANP) secretion and its modification in hypertrophied atria. Isolated perfused beating rat atria were used from control and isoproterenol-treated rats. Levosimendan and its metabolite OR-1896 caused a positive inotropic effect and suppressed ANP secretion in rat atria. Similar to levosimendan, the selective phosphodiesterase 3 (PDE3) or PDE4 inhibitor also suppressed ANP secretion...
April 10, 2018: European Journal of Pharmacology
Tommaso Prosdocimi, Luca Mollica, Stefano Donini, Marta S Semrau, Anna Paola Lucarelli, Egidio Aiolfi, Andrea Cavalli, Paola Storici, Silvana Alfei, Chiara Brullo, Olga Bruno, Emilio Parisini
Selected members of the large rolipram-related GEBR family of phosphodiesterase-4 (PDE4) inhibitors have been shown to facilitate long term potentiation (LTP) and improve memory functions without causing emetic-like behavior in rodents. Despite their micromolar-range binding affinities and their promising pharmacological and toxicological profiles, little if any structure-activity relationship studies have so far been carried out in order to elucidate the molecular bases of their action. Here, we report the crystal structure of a number of GEBR library compounds in complex with the catalytic domain of PDE4D as well as their inhibitory profiles for both the long PDE4D3 isoform and the catalytic domain alone...
April 13, 2018: Biochemistry
Esther Barreiro, Ester Puig-Vilanova, Anna Salazar-Degracia, Sergi Pascual-Guardia, Carme Casadevall, Joaquim Gea
Peripheral muscle weakness and mass loss are characteristic features in severe COPD. We hypothesized that the phosphodiesterase-4 inhibitor roflumilast-induced cAMP may ameliorate proteolysis and metabolism in skeletal muscles of COPD patients with severe muscle wasting. In myogenic precursor cells (isolated from muscle biopsies and cultured up to obtain differentiated myotubes) from 10 severe COPD patients and 10 healthy controls, which were treated with 1 microM roflumilast N-oxide (RNO) for three time-cohorts (1h, 6h, and 24h), genes of antioxidant defense and oxidative stress marker, myogenesis and muscle metabolism, proteolysis (tyrosine release assay) and ubiquitin-proteasome system markers, autophagy, and myosin isoforms were analyzed using RT-PCR and immunoblotting...
April 12, 2018: Journal of Applied Physiology
Rene Blöcher, Karen M Wagner, Raghavender R Gopireddy, Todd R Harris, Hao Wu, Bogdan Barnych, Sung Hee Hwang, Yang K Xiang, Ewgenij Proschak, Christophe Morisseau, Bruce D Hammock
Inspired by previously discovered enhanced analgesic efficacy between soluble epoxide hydrolase (sEH) and phosphodiesterase 4 (PDE4) inhibitors, we designed, synthesized and characterized 21 novel sEH/PDE4 dual inhibitors. The best of these displayed good efficacy in in vitro assays. Further pharmacokinetic studies of a subset of 4 selected compounds led to the identification of a bioavailable dual inhibitor N-(4-methoxy-2-(trifluoromethyl)benzyl)-1-propionylpiperidine-4-carboxamide (MPPA). In a lipopolysaccharide induced inflammatory pain rat model, MPPA rapidly increased in the blood (Tmax = 30 min; Cmax = 460 nM) after oral administration of 3 mg/kg and reduced inflammatory pain with rapid onset of action correlating with blood levels over a time course of 4 hours...
April 3, 2018: Journal of Medicinal Chemistry
Giulia Vigone, Leia C Shuhaibar, Jeremy R Egbert, Tracy F Uliasz, Matthew A Movsesian, Laurinda A Jaffe
Luteinizing hormone (LH) acts on the granulosa cells that surround the oocyte in mammalian preovulatory follicles to cause meiotic resumption and ovulation. Both of these responses are mediated primarily by an increase in cAMP in the granulosa cells, and activity of the cAMP phosphodiesterase PDE4 contributes to preventing premature responses. However, 2 other cAMP-specific phosphodiesterases, PDE7 and PDE8, are also expressed at high levels in the granulosa cells, raising the question of whether these phosphodiesterases also contribute to preventing uncontrolled activation of meiotic resumption and ovulation...
March 28, 2018: Endocrinology
Fu-Chao Liu, Huang-Ping Yu, Cheng-Yu Lin, Ahmed O Elzoghby, Tsong-Long Hwang, Jia-You Fang
BACKGROUND: Cilomilast is a phosphodiesterase 4 (PDE4) inhibitor for treating inflammatory lung diseases. This agent has a narrow therapeutic index with significant adverse effects on the nervous system. This study was conducted to entrap cilomilast into PEGylated phosphatidylcholine-rich niosomes (phosphatiosomes) to improve pulmonary delivery via the strong affinity to pulmonary surfactant film. Neutrophils were used as a cell model to test the anti-inflammatory activity of phosphatiosomes...
March 30, 2018: Journal of Nanobiotechnology
Manju Sharma, Corey Levenson, John C Browning, Emily M Becker, Ian Clements, Paul Castella, Michael E Cox
Cyclic adenosine monophosphate phosphodiesterases (PDEs) regulate pro-inflammatory cytokine production. One isoform, PDE4, is overactive in chronic relapsing inflammatory skin diseases: psoriasis and eczema/atopic dermatitis, and in several cancers. East Indian sandalwood oil (EISO) has significant anti-inflammatory properties. Here, we report that 75% of pediatric eczema/atopic dermatitis patients treated with topical EISO formulations achieved a >50% reduction in their Eczema Area and Severity Index score...
2018: Frontiers in Pharmacology
Souvik Dey, Suranjana Goswami, Alaa Eisa, Rahul Bhattacharjee, Cameron Brothag, Douglas Kline, Srinivasan Vijayaraghavan
The multifaceted glycogen synthase kinase (GSK3) has an essential role in sperm and male fertility. Since cyclic AMP (cAMP) plays an important role in sperm function, we investigated whether GSK3 and cAMP pathways may be interrelated. We used GSK3 and soluble adenylyl cyclase (sAC) knockout mice and pharmacological modulators to examine this relationship. Intracellular cAMP levels were found to be significantly lower in sperm lacking GSK3α or GSK3β. A similar outcome was observed when sperm cells were treated with SB216763, a GSK3 inhibitor...
March 25, 2018: Journal of Cellular Physiology
Yefei Pang, Peter Thomas
Natriuretic peptide type C (NPPC) and its receptor, natriuretic peptide receptor 2 (NPR2), have essential roles in maintaining meiotic arrest of oocytes in several mammalian species. However, it is not known if a similar mechanism exists in non-mammalian vertebrates. Using zebrafish as a model, we show that Nppc is expressed in ovarian follicle cells, whereas Npr2 is mainly detected in oocytes. Treatment of intact and defolliculated oocytes with 100 nM NPPC for 6 h caused a large increase in cGMP concentrations, and a significant decrease in oocyte maturation (OM), an effect that was mimicked by treatment with 8-Br-cGMP...
March 22, 2018: General and Comparative Endocrinology
Aya M Almatary, Mohammad A Elmorsy, Walaa M El Husseiny, Khalid B Selim, Magda A-A El-Sayed
A new hybrid template was designed by combining the structural features of phosphodiesterase 4 (PDE4) inhibitors with several heterocyclic moieties which present an integral part in the skeleton of many apoptotic agents. Thirteen compounds of the synthesized hybrids displayed higher inhibitory activity against PDE4B than the reference drug, roflumilast. Further investigation indicated that compounds 13b and 20 arrested the cell cycle at the G2/M phase and the pre-G1 phase, and induced cell death by apoptosis of A549 cells in a caspase-dependent manner...
March 24, 2018: Archiv der Pharmazie
Vicky Pauwelyn, Romain A Lefebvre
Background: As the signal transduction of 5-HT4 receptors on cholinergic neurons innervating smooth muscle is controlled by phosphodiesterase (PDE) 4 in porcine stomach and colon, and human large intestine, the in vivo gastroprokinetic effects of a 5-HT4 receptor agonist might be enhanced by combination with a selective PDE4 inhibitor. The presence of 5-HT4 receptors on cholinergic neurons towards murine gastrointestinal circular muscle was recently shown. If the control of this receptor pathway by PDE4 is also present in mice, this might be a good model for in vivo testing of the combination therapy...
2018: Frontiers in Pharmacology
Ángel Agis-Torres, Paz Recio, María Elvira López-Oliva, María Pilar Martínez, María Victoria Barahona, Sara Benedito, Salvador Bustamante, Miguel Ángel Jiménez-Cidre, Albino García-Sacristán, Dolores Prieto, Vítor S Fernandes, Medardo Hernández
Nitric oxide (NO) and hydrogen sulfide (H2 S) play a pivotal role in nerve-mediated relaxation of the bladder outflow region. In the bladder neck, a marked phosphodiesterase type 4 (PDE4) expression has also been described and PDE4 inhibitors, as rolipram, produce smooth muscle relaxation. This study investigates the role of PDE4 isoenzyme in bladder neck gaseous inhibitory neurotransmission. We used Western blot and double immunohistochemical staining for the detection of NPP4 (PDE4) and PDE4A and organ baths for isometric force recording to roflumilast and tadalafil, PDE4 and PDE5, respectively, inhibitors in pig and human samples...
March 16, 2018: Scientific Reports
Yixian Liao, Yiming Guo, Sumei Li, Lei Wang, Yongmei Tang, Tianmiao Li, Weihao Chen, Guohua Zhong, Gaopeng Song
This paper describes our medicinal chemistry efforts on 7-(cyclopentyloxy)-6-methoxy1,2,3,4-tetrahydroisoquinoline scaffold: design, synthesis and biological evaluation using conformational restriction approach and bioisosteric replacement strategy. Biological data revealed that the majority of the synthesized compounds of this series displayed moderate to potent inhibitory activity against PDE4B and strong inhibition of LPS-induced TNFα release. Among them, compound 19 exhibited the strongest inhibition against PDE4B with an IC50 of 0...
March 6, 2018: Bioorganic & Medicinal Chemistry Letters
Richard S Roberts, Sara Sevilla, Manel Ferrer, Joan Taltavull, Begoña Hernández, Victor Segarra, Jordi Gracia, Martin D Lehner, Amadeu Gavaldà, Míriam Andrés, Judit Cabedo, Dolors Vilella, Peter Eichhorn, Elena Calama, Carla Carcasona, Montserrat Miralpeix
Rational design of a novel template of naphthyridinones rapidly led to PDE4 inhibitors with sub-nanomolar enzymatic potencies. X-ray crystallography confirmed the binding mode of this novel template. We achieved compounds with double-digit picomolar enzymatic potencies through further structure-based design by targeting both the PDE4 enzyme metal-binding pocket and occupying the solvent-filled pocket. A strategy for lung retention and long duration of action based on low aqueous solubility was followed. In vivo efficacies were measured in a rat lung neutrophilia model by suspension microspray and dry powder administration...
March 5, 2018: Journal of Medicinal Chemistry
Jian Luo, Ling Yang, Jing Yang, Dan Yang, Bi-Cui Liu, Dan Liu, Bin-Miao Liang, Chun-Tao Liu
Phosphodiesterase 4 (PDE4) inhibitors are a novel medication approved for airway inflammatory diseases including chronic obstructive pulmonary disease. Their role and application in asthma are controversial and not defined. A comprehensive search was performed in major databases (1946-2016) using the keywords: 'phosphodiesterase 4 inhibitor' or 'roflumilast' and 'asthma'. Placebo-controlled trials reporting lung function, airway hyperresponsiveness by direct challenge, asthma control and exacerbations, and adverse events were included...
March 4, 2018: Respirology: Official Journal of the Asian Pacific Society of Respirology
Jiahong Zhong, Hui Yu, Chang Huang, Qiuping Zhong, Yaping Chen, Jinfeng Xie, Zhongzhen Zhou, Jiangping Xu, Haitao Wang
Phosphodiesterase 4 (PDE4) is a promising target for the treatment of Parkinson's disease (PD). However, the underlying mechanism has not yet been well elucidated. Additionally, most of current PDE4 inhibitors produce severe nausea and vomiting response in patients, which limit their clinical application. FCPR16 is a novel PDE4 inhibitor with little emetic potential. In the present study, the neuroprotective effect and underlying mechanism of FCPR16 against cellular apoptosis induced by 1-methyl-4-phenylpyridinium (MPP+ ) were examined in SH-SY5Y cells...
February 14, 2018: Redox Biology
Yuri A Blednov, Adriana J Da Costa, Tamara Tarbox, Olga Ponomareva, Robert O Messing, R Adron Harris
BACKGROUND: Phosphodiesterase type 4 (PDE4) inhibitors produce widespread anti-inflammatory effects and reduce ethanol consumption in several rodent models. These drugs are potential treatments for several diseases, including central nervous system disorders, but clinical use is limited by their emetic activity. Apremilast is a selective PDE4 inhibitor with fewer gastrointestinal side effects that is FDA approved for the treatment of psoriasis. METHODS: We measured the acute and chronic effects of apremilast on ethanol consumption in male and female C57BL/6J mice using the continuous and intermittent 24-h two-bottle choice drinking models...
February 22, 2018: Alcoholism, Clinical and Experimental Research
Chen Xie, Ana Ramirez, Zhijun Wang, Moses S S Chow, Jijun Hao
Allosteric phosphodiesterase 4 (PDE4) inhibitors are highly sought after due to their important anti-inflammatory and anti-cancer therapeutic effects. We recently identified Eggmanone, an extraordinarily selective allosteric PDE4 inhibitor displaying favorable drug properties. However, a specific analytic method of Eggmanone in serum and its pharmacokinetics have not been reported yet. In this study, we developed a rapid and sensitive high performance liquid chromatography-mass spectrometric (HPLC-MS/MS) method to determine Eggmanone concentrations in rat plasma...
February 11, 2018: Journal of Pharmaceutical and Biomedical Analysis
Michael D Howell, Carolyn Fitzsimons, Paul A Smith
OBJECTIVE: To provide an overview of janus kinase (JAK), chemoattractant receptor homologous molecule expressed on TH 2 cells (CRTH2), and phosphodiesterase 4 (PDE4) inhibitors in allergic disorders. DATA SOURCES: PubMed literature review. STUDY SELECTIONS: Articles included in this review discuss the emerging mechanism of action of small molecule inhibitors and their use in the treatment of atopic dermatitis (AD), asthma, and allergic rhinitis (AR)...
April 2018: Annals of Allergy, Asthma & Immunology
Akihiro Takano, Tolga Uz, Jesus Garcia-Segovia, Max Tsai, Gezim Lahu, Nahid Amini, Ryuji Nakao, Zhisheng Jia, Christer Halldin
PURPOSE: Phosphodiesterase 4 (PDE4) inhibition in the brain has been reported to improve cognitive function in animal models. Therefore, PDE4 inhibitors are one of key targets potential for drug development. Investigation of brain PDE4 occupancy would help to understand the effects of PDE4 inhibition to cognitive functions. Roflumilast is a selective phosphodiesterase type 4 (PDE4) inhibitor used clinically for severe chronic obstructive pulmonary disease, but the effects to the brain have not been well investigated...
February 13, 2018: Molecular Imaging and Biology: MIB: the Official Publication of the Academy of Molecular Imaging
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