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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
Jihyun Youm, Hyunyong Lee, Youngwoo Choi, Joobyoung Yoon
Our previous study revealed that the ethanolic extract of Justicia procumbens ameliorates ovalbumin-induced airway inflammation and airway hyper-responsiveness in a mouse model of asthma. However, the mechanism of action of the extract remains unknown. In this study, we prepared DW2008S, an optimized and standardized powder extracted from J. procumbens using anhydrous ethanol, and investigated its anti-asthmatic effect and mechanism of action. Our results showed that DW2008S contains two major ingredients, justicidin A (JA) and justicidin B (JB), which selectively inhibit T helper 2 (Th2) cell responses in concanavalin A-activated spleen cells and polarized Th2 cells...
March 7, 2018: Journal of Cellular and Molecular Medicine
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
Lin Chen, Gui-Hua Tang, Fu-Liang Guo, Wei Li, Jun-Sheng Zhang, Bo Liu, Sheng Yin
A pair of undescribed bicoumarin enantiomers, (P)/(M)-corinepalensin A, two undescribed prenylated coumarins, corinepalensins B and C, along with ten known coumarins were isolated from the twigs of Coriaria nepalensis. (P)/(M)-corinepalensin A feature a rare C-5C-5' axially chiral linkage between two prenylated coumarin monomers. Their structures were determined by a combination of spectroscopic methods, single crystal X-ray diffraction, and ECD calculations. All isolates were evaluated for the inhibitory activity against phosphodiesterase-4 (PDE4), which is a drug target for the treatment of asthma and chronic obstructive pulmonary disease...
February 28, 2018: Phytochemistry
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 Smith
OBJECTIVE: To provide an overview of janus kinase (JAK), chemoattractant receptor-homologous molecule expressed on T-helper 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 utilization in atopic dermatitis (AD), asthma, and allergic rhinitis (AR)...
February 14, 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
Maarten Ooms, Tetsuya Tsujikawa, Talakad G Lohith, Sanché N Mabins, Sami S Zoghbi, Akiko Sumitomo, Hanna Jaaro-Peled, Yasuyuki Kimura, Sanjay Telu, Victor W Pike, Toshifumi Tomoda, Robert B Innis, Akira Sawa, Masahiro Fujita
Although still a matter of controversy, disrupted in schizophrenia protein 1 (DISC1) was suggested as a potential inhibitor of phosphodiesterase 4 (PDE4). We used Disc1 locus impairment (LI) mice to investigate the interaction between PDE4 and DISC 1 in vivo and in vitro. [11C]( R)-Rolipram binding was measured by PET in LI ( n = 11) and C57BL/6 wild-type (WT, n = 9) mice. [11C]( R)-Rolipram total distribution volumes ( VT) were calculated and corrected for plasma-free fraction ( fP) measured in a separate group of LI ( n = 6) and WT ( n = 7) mice...
January 1, 2018: Journal of Cerebral Blood Flow and Metabolism
Yu-Chen Hsu, Shu-An Hsieh, Po-Hsuan Li, Rai-Shung Liu
This work describes new N,O-functionalization of 1,4-diyn-3-ols with N-hydroxyanilines to yield highly functionalized pyrrole derivatives. In a postulated mechanism, N-hydroxyaniline attacks the more electron-rich alkynes via regioselective N-attack to form unstable ketone-derived nitrones that react with their tethered alkynes via an intramolecular oxygen-transfer to form α-oxo gold carbenes. This new method is applicable to a short synthesis of a bioactive molecule, a PDE4 inhibitor.
February 8, 2018: Chemical Communications: Chem Comm
Hui Yu, Zhengqiang Zou, Xiaolin Zhang, Wanli Peng, Chen Chen, Yicheng Ye, Jiangping Xu, Haitao Wang
Inflammatory responses induced by peripheral administration of lipopolysaccharide (LPS) triggers depressive-like behavioral syndrome in rodents. Inhibition of phosphodiesterase 4 (PDE4) produces a robust anti-inflammatory effect in inflammatory cells. Unfortunately, archetypal PDE4 inhibitors cause intolerable gastrointestinal side-effects, such as vomiting and nausea. N-isopropyl-3-(cyclopropylmethoxy)-4-difluoromethoxy benzamide (FCPR03) is a novel, selective PDE4 inhibitor with little, or no, emetic potency...
February 8, 2018: International Journal of Molecular Sciences
Grażyna Chłoń-Rzepa, Agnieszka Jankowska, Marietta Ślusarczyk, Artur Świerczek, Krzysztof Pociecha, Elżbieta Wyska, Adam Bucki, Alicja Gawalska, Marcin Kołaczkowski, Maciej Pawłowski
A novel butanehydrazide derivatives of purine-2,6-dione designed using a ligand-based approach were synthesized and their in vitro activity against both PDE4B and PDE7A isoenzymes was assessed. The 7,8-disubstituted purine-2,6-dione derivatives 31, 34, 37, and 40 appeared to be the most potent PDE4/7 inhibitors with IC50 values in the range of that of the reference rolipram and BRL-50481, respectively. Moreover, docking studies explained the importance of N-(2,3,4-trihydroxybenzylidene)butanehydrazide substituent in position 7 of purine-2,6-dione core for dual PDE4/7 inhibitory properties...
January 27, 2018: European Journal of Medicinal Chemistry
Chantal Barberot, Aurélie Moniot, Ingrid Allart-Simon, Laurette Malleret, Tatiana Yegorova, Marie Laronze-Cochard, Abderrazzaq Bentaher, Maurice Médebielle, Jean-Philippe Bouillon, Eric Hénon, Janos Sapi, Frédéric Velard, Stéphane Gérard
Cyclic nucleotide phosphodiesterase type 4 (PDE4), that controls intracellular level of cyclic nucleotide cAMP, has aroused scientific attention as a suitable target for anti-inflammatory therapy in respiratory diseases. Here we describe the development of two families of pyridazinone derivatives as potential PDE4 inhibitors and their evaluation as anti-inflammatory agents. Among these derivatives, 4,5-dihydropyridazinone representatives possess promising activity, selectivity towards PDE4 isoenzymes and are able to reduce IL-8 production by human primary polymorphonuclear cells...
January 17, 2018: European Journal of Medicinal Chemistry
E Papadavid, N Rompoti, K Theodoropoulos, G Kokkalis, D Rigopoulos
BACKGROUND: Psoriasis is a chronic inflammatory skin disease, which requires long term, safe and effective treatment. Apremilast, a small-molecule PDE4 inhibitor, has been introduced as psoriasis (and psoriatic arthritis) treatment in Europe in 2015. OBJECTIVE: We analysed and report the efficacy and safety of apremilast in the first 51 patients with psoriasis that have undergone treatment with this novel small molecule in our outpatient clinic. METHOD: Our primary endpoint was the evaluation of clinical response to apremilast according to the percentage of PASI reduction (ΔPASI) at 16 weeks after treatment initiation...
February 1, 2018: Journal of the European Academy of Dermatology and Venereology: JEADV
Bracy A Fertig, George S Baillie
cAMP is the archetypal and ubiquitous second messenger utilised for the fine control of many cardiovascular cell signalling systems. The ability of cAMP to elicit cell surface receptor-specific responses relies on its compartmentalisation by cAMP hydrolysing enzymes known as phosphodiesterases. One family of these enzymes, PDE4, is particularly important in the cardiovascular system, where it has been extensively studied and shown to orchestrate complex, localised signalling that underpins many crucial functions of the heart...
January 31, 2018: Journal of Cardiovascular Development and Disease
J Mokry, A Urbanova, I Medvedova, M Kertys, P Mikolka, P Kosutova, D Mokra
Selective phosphodiesterase (PDE) 4 inhibitors have recently been introduced into the therapy of chronic obstructive pulmonary disease. However, suppression of airway reactivity and eosinophilic inflammation by increased intracellular cAMP could be beneficial in bronchial asthma as well. PDE5 inhibitors are used for the therapy of erectile dysfunction, pulmonary hypertension, and other cardiovascular diseases, but an expression of PDE5 in several immune cells suggests its perspectives in inflammation, as well...
October 2017: Journal of Physiology and Pharmacology: An Official Journal of the Polish Physiological Society
Evangelia Papadavid, Georgios Kokkalis, Georgios Polyderas, Konstantinos Theodoropoulos, Dimitrios Rigopoulos
Background: Apremilast is a new immunomodulatory drug, a small molecule inhibitor of PDE4, which down-regulates the expression of multiple pro-inflammatory cytokines, such as tumor necrosis factor alpha, interleukin 17, interleukin 23. Main observations: We describe a case of a 54-year-old man with erythroderma in the course of psoriasis (PASI=49), with contraindications to other psoriasis therapies, in whom total clearance of skin lesions was achieved by day 20 after therapy with apremilast at a dose of 30 mg bid (ΔPASI = 100)...
December 1, 2017: Journal of Dermatological Case Reports
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