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https://www.readbyqxmd.com/read/28800229/fragment-based-drug-discovery-of-phosphodiesterase-inhibitors
#1
Fredrik Svensson, Andreas Bender, David Bailey
Phosphodiesterases are proving to be fruitful targets for drug discovery. At the same time fragment-based drug discovery has matured into a powerful and widely applied technique. In this communication we review the application of fragment-based drug discovery for the successful identification of novel 3',5'-cyclic nucleotide phosphodiesterase (PDE) inhibitors, concentrating on both experimental and computational strategies for fragment screening and hit-to-lead development. To this end, we also mine the open access databases ChEMBL and PDB for fragments showing PDE inhibitory activity, as well as SureChEMBL for recent PDE related patents, to provide a wider context for exploring fragment diversity...
August 11, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28799255/synergy-between-5-ht4-receptor-stimulation-and-phosphodiesterase-4-inhibition-in-facilitating-acetylcholine-release-in-human-large-intestinal-circular-muscle
#2
V Pauwelyn, W Ceelen, R A Lefebvre
BACKGROUND: Gastroprokinetic properties of 5-HT4 receptor agonists, such as prucalopride, are attributed to activation of 5-HT4 receptors on cholinergic nerves innervating smooth muscle in the gastrointestinal smooth muscle layer, increasing acetylcholine release and muscle contraction. In porcine stomach and colon, phosphodiesterase (PDE) 4 has been shown to control the signaling pathway of these 5-HT4 receptors. The aim of this study was to investigate the PDE-mediated control of these 5-HT4 receptors in human large intestine...
August 10, 2017: Neurogastroenterology and Motility: the Official Journal of the European Gastrointestinal Motility Society
https://www.readbyqxmd.com/read/28798156/phosphodiesterase-4-inhibitor-and-phosphodiesterase-5-inhibitor-combination-therapy-has-antifibrotic-and-anti-inflammatory-effects-in-mdx-mice-with-duchenne-muscular-dystrophy
#3
Yasunori Nio, Masayuki Tanaka, Yoshihiko Hirozane, Yo Muraki, Mitsugi Okawara, Masatoshi Hazama, Takanori Matsuo
Duchenne muscular dystrophy (DMD) is the most common inherited muscular dystrophy. Patients experience DMD in their 20s from cardiac or respiratory failure related to progressive muscle wasting. Currently, the only treatments for the symptoms of DMD are available. Muscle fibrosis, a DMD feature, leads to reduced muscle function and muscle mass, and hampers pharmaceutical therapeutic efficacy. Although antifibrotic agents may be useful, none is currently approved. Phosphodiesterase (PDE)-4 inhibitors have exhibited antifibrotic effects in human and animal models...
August 10, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28796496/discovery-of-clinical-candidate-n-1s-1-3-fluoro-4-trifluoromethoxy-phenyl-2-methoxyethyl-7-methoxy-2-oxo-2-3-dihydropyrido-2-3-b-pyrazine-4-1h-carboxamide-tak-915-a-highly-potent-selective-and-brain-penetrating-phosphodiesterase-2a-inhibitor-for-the-treatment
#4
Satoshi Mikami, Shinji Nakamura, Tomoko Ashizawa, Izumi Nomura, Masanori Kawasaki, Shigekazu Sasaki, Hideyuki Oki, Hironori Kokubo, Isaac D Hoffman, Hua Zou, Noriko Uchiyama, Kosuke Nakashima, Naomi Kamiguchi, Haruka Imada, Noriko Suzuki, Hiroki Iwashita, Takahiko Taniguchi
Phosphodiesterase (PDE) 2A inhibitors have emerged as a novel mechanism with potential therapeutic option to ameliorate cognitive dysfunction in schizophrenia or Alzheimer's disease through upregulation of cyclic nucleotides in the brain, and thereby achieve potentiation of cyclic nucleotide signaling pathways. This article details the expedited optimization of our recently disclosed pyrazolo[1,5-a]pyrimidine lead compound 4b, leading to the discovery of clinical candidate 36 (TAK-915), which demonstrates an appropriate combination of potency, PDE selectivity, and favorable pharmacokinetic (PK) properties, including brain penetration...
August 10, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28772081/investigational-phosphodiesterase-inhibitors-in-phase-i-and-phase-ii-clinical-trials-for-alzheimer-s-disease
#5
Jos Prickaerts, Pim R A Heckman, Arjan Blokland
Phosphodiesterase (PDE) inhibitors improve signaling pathways in brain circuits by increasing intracellular cyclic adenosine monophosphate (cAMP) and/or cyclic guanosine monophosphate (cGMP). In the last decade, the first clinical studies investigating selective PDE inhibitors in Alzheimer's disease (AD) have been initiated, based on their positive effects on cognitive processes and neuroprotection in numerous animal studies. Areas covered: This article reviews the clinical studies investigating the pro-cognitive/neuroprotective effects of PDE inhibitors in patients with AD, as well as in age-associated memory impaired elderly and patients with mild cognitive impairment (MCI), the prodromal stage of AD...
August 3, 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28761827/spectroscopic-and-spectrometric-methods-used-for-the-screening-of-certain-herbal-food-supplements-suspected-of-adulteration
#6
Cristina Mateescu, Anca Mihaela Popescu, Gabriel Lucian Radu, Tatiana Onisei, Adina Elena Raducanu
Purpose: This study was carried out in order to find a reliable method for the fast detection of adulterated herbal food supplements with sexual enhancement claims. As some herbal products are advertised as "all natural", their "efficiency" is often increased by addition of active pharmaceutical ingredients such as PDE-5 inhibitors, which can be a real health threat for the consumer. Methodes: Adulterants, potentially present in 50 herbal food supplements with sexual improvement claims, were detected using 2 spectroscopic methods - Raman and Fourier Transform Infrared - known for reliability, reproductibility, and an easy sample preparation...
June 2017: Advanced Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/28759228/discovery-of-an-orally-bioavailable-brain-penetrating-in-vivo-active-phosphodiesterase-2a-inhibitor-lead-series-for-the-treatment-of-cognitive-disorders
#7
Satoshi Mikami, Shigekazu Sasaki, Yasutomi Asano, Osamu Ujikawa, Shoji Fukumoto, Kosuke Nakashima, Hideyuki Oki, Naomi Kamiguchi, Haruka Imada, Hiroki Iwashita, Takahiko Taniguchi
Herein, we describe the discovery of a potent, selective, brain-penetrating, in vivo active phosphodiesterase (PDE) 2A inhibitor lead series. To identify high-quality leads suitable for optimization and enable validation of the physiological function of PDE2A in vivo, structural modifications of the high-throughput screening hit 18 were performed. Our lead generation efforts revealed three key potency-enhancing functionalities with minimal increases in molecular weight (MW) and no change in topological polar surface area (TPSA)...
July 31, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28754627/therapeutic-potentials-of-natural-compounds-acting-on-cyclic-nucleotide-phosphodiesterase-families
#8
REVIEW
Abdurazzag Abusnina, Claire Lugnier
Intracellular cyclic AMP and/or cyclic GMP are characterized in the 1960th. These second messengers, hydrolysed specifically by cyclic nucleotide phosphodiesterase (PDE), play a major role in intracellular signalling. Natural products have been a rich source of drug discovery, Theophylline and Methylxanthine originated from tea leaves used for asthma treatment, whereas, Papaverine, a natural isoquinolein originated from Papaver somniferum traditionally used in impotency, altogether as caffeine where firstly described as PDE-inhibiting compounds...
July 25, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28753652/the-phosphodiesterase-inhibitor-ibudilast-attenuates-neuroinflammation-in-the-mptp-model-of-parkinson-s-disease
#9
Joanna Schwenkgrub, Malgorzata Zaremba, Ilona Joniec-Maciejak, Agnieszka Cudna, Dagmara Mirowska-Guzel, Iwona Kurkowska-Jastrzębska
BACKGROUND/AIMS: Since the degeneration of the nigrostriatal dopaminergic pathway in Parkinson's disease (PD) is associated with the inflammation process and decreased levels of cyclic nucleotides, inhibition of up-regulated cyclic nucleotide phosphodiesterases (PDEs) appears to be a promising therapeutic strategy. We used ibudilast (IBD), a non-selective PDE3,4,10,11 inhibitor, due to the abundant PDE 4 and 10 expression in the striatum. The present study for the first time examined the efficacy of IBD in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD...
2017: PloS One
https://www.readbyqxmd.com/read/28747647/delivery-of-intracavernosal-therapies-using-needle-free-injection-devices
#10
D O'Kane, L Gibson, J du Plessis, A Davidson, D Bolton, N Lawrentschuk
ED affects a significant proportion of males worldwide. With an ever-aging population the prevalence of ED is predicted to double in the next decade. Oral PDE-5 inhibitors are the first-line treatment for ED and have revolutionised its management. These agents are however ineffective in some men. Intracavernosal injection (ICI) of vasoactive agents is an effective second-line therapy for ED. Despite proven efficacy, needle phobia and anxiety with self-needling limit the use of intracavernosal (IC) therapies...
July 27, 2017: International Journal of Impotence Research
https://www.readbyqxmd.com/read/28737056/quantification-of-human-brain-pde4-occupancy-by-gsk356278-a-11-c-r-rolipram-pet-study
#11
Jasper van der Aart, Cristian Salinas, Rahul Dimber, Sabina Pampols-Maso, Ashley A Weekes, John Tonkyn, Frank A Gray, Jan Passchier, Roger N Gunn, Eugenii A Rabiner
We characterized the relationship between the plasma concentration of the phospodiesterase (PDE)-4 inhibitor GSK356278 and occupancy of the PDE4 enzyme in the brain of healthy volunteers, using the positron emission tomography (PET) tracer [(11)C](R)-rolipram. To this end, PET scans were acquired in eight male volunteers before and at 3 and 8 h after a single 14 mg oral dose of GSK356278. A metabolite-corrected arterial input function was used in conjunction with the dynamic PET emission data to estimate volumes of distribution (VT) from a two-tissue compartment model...
January 1, 2017: Journal of Cerebral Blood Flow and Metabolism
https://www.readbyqxmd.com/read/28730281/pk-pd-studies-on-non-selective-pde-inhibitors-in-rats-using-camp-as-a-marker-of-pharmacological-response
#12
Artur Świerczek, Elżbieta Wyska, Sebastian Baś, Marta Woyciechowska, Jacek Mlynarski
In recent years, phosphodiesterase (PDE) inhibitors have been frequently tested for the treatment of experimental inflammatory and immune disorders. It is suggested that anti-inflammatory properties of PDE inhibitors are related to their ability to increase cAMP levels. The aim of this study was to verify the hypothesis that cAMP may be a useful marker of pharmacological response following administration of non-selective PDE inhibitors (pentoxifylline and (±)-lisofylline) to endotoxemic rats. Male Wistar rats were administered LPS (1 mg kg(-1), i...
July 20, 2017: Naunyn-Schmiedeberg's Archives of Pharmacology
https://www.readbyqxmd.com/read/28713578/retrospective-evaluation-of-pimobendan-and-sildenafil-therapy-for-severe-pulmonary-hypertension-due-to-lung-disease-and-hypoxia-in-28-dogs-2007-2013
#13
Lisa A Murphy, Nicholas Russell, Domenico Bianco, Reid K Nakamura
Pulmonary hypertension (PH) is the persistent abnormal increase in pulmonary artery (PA) pressure and in dogs is usually secondary to congenital disease causing pulmonary over circulation, chronic respiratory disease and elevated left atrial pressure. Sildenafil (SF) is a phosphodiesterase (PDE) V inhibitor that causes pulmonary artery (PA) vasodilation by increasing pulmonary vascular concentrations of cyclic guanosine monophosphate which subsequently increases the activity of endogenous nitric oxide. Pimobendan (PB) is a PDE III inhibitor with calcium sensitizing effects thereby exerting positive inotropy and vasodilation...
May 2017: Veterinary Medicine and Science
https://www.readbyqxmd.com/read/28709568/current-and-emerging-topical-therapies-for-atopic-dermatitis
#14
Jeremy Udkoff, Andrea Waldman, Jusleen Ahluwalia, Jenna Borok, Lawrence F Eichenfield
The pathogenesis of atopic dermatitis (AD) involves epidermal barrier dysfunction and T helper cell type 2 (Th2) lymphocyte-driven inflammation. Cytokines, such as interleukin 4 (IL-4) and IL-13, are important in this reaction. They stimulate B cells to produce immunoglobulin E, causing atopic disease. This process has been well characterized, and new therapies for AD, such as phosphodiesterase 4 (PDE-4) inhibitors, Th2-expressed chemoattractant receptor-homologous molecule antagonists, and Janus kinase inhibitors, work by antagonizing this cellular pathway...
July 2017: Clinics in Dermatology
https://www.readbyqxmd.com/read/28706457/relaxant-and-anti-inflammatory-effect-of-two-thalidomide-analogs-as-pde-4-inhibitors-in-pregnant-rat-uterus
#15
Víctor Manuel Muñoz-Pérez, Eduardo Fernández-Martínez, Héctor Ponce-Monter, Mario I Ortiz
The aim of this study was to evaluate the relaxant and anti-inflammatory effects of two thalidomide analogs as phosphodiesterase-4 (PDE-4) inhibitors in pregnant rat uterus. Uteri from Wistar female rats were isolated at 19 day of pregnancy. Uterine samples were used in functional studies to evaluate the inhibitory effects of the thalidomide analogs, methyl 3-(4-nitrophthalimido)-3-(3,4-dimethoxyphenyl)-propanoate (4NO2PDPMe) and methyl 3-(4-aminophthalimido)-3-(3,4-dimethoxyphenyl)-propanoate (4APDPMe), on prostaglandin-F2α (PGF2α)-induced phasic, K(+)-induced tonic, and Ca(2+)-induced contractions...
July 2017: Korean Journal of Physiology & Pharmacology
https://www.readbyqxmd.com/read/28702718/single-center-experience-using-selexipag-in-a-pediatric-population
#16
Roberto Gallotti, Diana E Drogalis-Kim, Gary Satou, Juan Alejos
Pulmonary arterial hypertension (PAH) is a rare and progressive disorder. Current treatment in the pediatric population includes phosphodiesterase 5 inhibitors (PDE-5i), endothelin receptor antagonists (ERA), and both inhaled and intravenous prostacyclin pathway agonists. As of December 22, 2015 the first oral prostacyclin pathway agonist, selexipag (Uptravi(®)), was FDA approved in the US. In this case series, we discuss our single-center experience using selexipag in a pediatric population, composed of both patients with idiopathic PAH, and patients with congenital heart disease and PAH...
July 13, 2017: Pediatric Cardiology
https://www.readbyqxmd.com/read/28701798/cognitive-behavioral-therapy-as-an-adjunct-treatment-for-pakistani-men-with-ed
#17
S Khan, A Amjad, D Rowland
The goal of this study was to determine potential positive effects of cognitive behavioral therapy (CBT) on Pakistani men with ED who were undergoing treatment with a PDE-5 inhibitor. We used a pre-post research design comparing men with and without adjunctive CBT. Men in the two groups were compared to determine whether CBT improved sexual function, as measured by the International Index of Erectile Function (IIEF). A total of 60 individuals diagnosed with ED completed the study. Participants were systematically assigned to one of two groups, the CBT group or the control group...
July 13, 2017: International Journal of Impotence Research
https://www.readbyqxmd.com/read/28697992/pde3-inhibition-by-c-type-natriuretic-peptide-induced-cgmp-enhances-camp-mediated-signaling-in-both-non-failing-and-failing-hearts
#18
Silja Meier, Kjetil Wessel Andressen, Jan Magnus Aronsen, Ivar Sjaastad, Karina Hougen, Tor Skomedal, Jan-Bjørn Osnes, Eirik Qvigstad, Finn Olav Levy, Lise Román Moltzau
We have previously shown that the natriuretic peptide receptor B (NPR-B) agonist C-type natriuretic peptide (CNP) enhances cyclic adenosine 3´,5´-monophosphate (cAMP)-mediated signaling in failing hearts, through cyclic guanosine 3´,5´-monophosphate (cGMP)-mediated phosphodiesterase (PDE) 3 inhibition. As several signaling pathways are importantly changed in failing hearts, it could not be taken for granted that this crosstalk would be the same in non-failing hearts. Thus, we wanted to clarify to which extent this effect of CNP occurred also in non-failing hearts...
July 8, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28689812/ibmx-protects-human-proximal-tubular-epithelial-cells-from-hypoxic-stress-through-suppressing-hypoxia-inducible-factor-1%C3%AE-expression
#19
Arif Ul Hasan, Wararat Kittikulsuth, Fuminori Yamaguchi, Tuba Musarrat Ansary, Asadur Rahman, Yuki Shibayama, Daisuke Nakano, Hirofumi Hitomi, Masaaki Tokuda, Akira Nishiyama
Hypoxia predisposes renal fibrosis. This study was conducted to identify novel approaches to ameliorate the pathogenic effect of hypoxia. Using human proximal tubular epithelial cells we showed that a pan-phosphodiesterase (PDE) inhibitor, 3-isobutyl-1-methylxanthine (IBMX) dose and time dependently downregulated hypoxia-inducible factor 1α (HIF-1α) mRNA expression, which was further augmented by addition of a transcriptional inhibitor, actinomycin D. IBMX also increased the cellular cyclic adenosine monophosphate (cAMP) level...
July 6, 2017: Experimental Cell Research
https://www.readbyqxmd.com/read/28687079/expression-and-function-of-phosphodiesterases-pdes-in-the-rat-urinary-bladder
#20
Xiaofei Zhu, Kui Zhai, Yue Mi, Guangju Ji
BACKGROUND: It has been shown that hosphodiesterases (PDEs) play an important role in mediating the smooth muscle tone of rat urinary bladder. However, the gene expression profiles of them were still unknown. METHODS: Urinary bladder Strips were obtained from both neonatal and adult Sprague-Dawley rats. RT-PCR/western blot and organ bath were used to measure the expression and function of PDEs. RESULTS: Adult rat urinary bladder expressed various PDE mRNA with the following rank order: PDE5A ≈ PDE9A ≈ PDE10A > PDE2A ≈ PDE4A ≈ PDE4D > PDE4B ≈ PDE3B ≈ PDE8B ≈ PDE7A ≈ PDE7B > PDE1A...
July 7, 2017: BMC Urology
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