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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/28768512/theory-of-synergistic-effects-hill-type-response-surfaces-as-null-interaction-models-for-mixtures
#6
Michael Schindler
BACKGROUND: The classification of effects caused by mixtures of agents as synergistic, antagonistic or additive depends critically on the reference model of 'null interaction'. Two main approaches are currently in use, the Additive Dose (ADM) or concentration addition (CA) and the Multiplicative Survival (MSM) or independent action (IA) models. We compare several response surface models to a newly developed Hill response surface, obtained by solving a logistic partial differential equation (PDE)...
August 2, 2017: Theoretical Biology & Medical Modelling
https://www.readbyqxmd.com/read/28763477/spatially-localized-phosphorous-metabolism-of-skeletal-muscle-in-duchenne-muscular-dystrophy-patients-24-month-follow-up
#7
M T Hooijmans, N Doorenweerd, C Baligand, J J G M Verschuuren, I Ronen, E H Niks, A G Webb, H E Kan
OBJECTIVES: To assess the changes in phosphodiester (PDE)-levels, detected by 31P magnetic resonance spectroscopy (MRS), over 24-months to determine the potential of PDE as marker for muscle tissue changes in Duchenne Muscular Dystrophy (DMD) patients. METHODS: Spatially resolved phosphorous datasets were acquired in the right lower leg of 18 DMD patients (range: 5-15.4 years) and 12 age-matched healthy controls (range: 5-14 years) at three time-points (baseline, 12-months, and 24-months) using a 7T MR-System (Philips Achieva)...
2017: PloS One
https://www.readbyqxmd.com/read/28761827/spectroscopic-and-spectrometric-methods-used-for-the-screening-of-certain-herbal-food-supplements-suspected-of-adulteration
#8
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/28759289/treatment-of-pseudoxanthoma-elasticum-like-papillary-dermal-elastolysis-with-non-ablative-fractional-resurfacing-laser-resulting-in-clinical-and-histologic-improvement-in-elastin-and-collagen
#9
Kristen Foering, Richard Lawrence Torbeck, Michael P Frank, Nazanin Saedi
OBJECTIVE: Pseudoxanthoma Elasticum-Like Papillary Dermal Elastolysis (PXE-PDE) is a rare skin condition seen predominantly in elderly females. These asymptomatic lesions are brought to the dermatologist's attention due to patient's displeasure in their appearance. We report a case of a 28-year old female with PXE-PDE on the right neck treated with Non-Ablative Fractional Resurfacing (NAFR). CASE: The patient on examination had yellow to skin-colored papules that coalesced into a cobblestone-appearing plaque on her lateral neck...
July 31, 2017: Journal of Cosmetic and Laser Therapy: Official Publication of the European Society for Laser Dermatology
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
#10
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
#11
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
#12
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
#13
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/28747437/crystal-structure-of-the-human-pol%C3%AF%C2%B5-b-subunit-in-complex-with-the-c-terminal-domain-of-the-catalytic-subunit
#14
Andrey G Baranovskiy, Jianyou Gu, Nigar D Babayeva, Igor Kurinov, Youri I Pavlov, Tahir H Tahirov
The eukaryotic B-family DNA polymerases include four members, Polα, Polδ, Polϵ, and Polζ, which share common architectural features, such as the exonuclease/polymerase and C-terminal domains (CTDs) of catalytic subunits bound to indispensable B-subunits, which serve as scaffolds that mediate interactions with other components of the replication machinery. Crystal structures for the B-subunits of Polα and Polδ/Polζ have been reported; the former within the primosome and separately with CTD, and the latter with the N-terminal domain (NTD) of the C-subunit...
July 26, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28747210/the-medical-food-souvenaid-affects-brain-phospholipid-metabolism-in-mild-alzheimer-s-disease-results-from-a-randomized-controlled-trial
#15
Anne Rijpma, Marinette van der Graaf, Marieke M Lansbergen, Olga Meulenbroek, Aysun Cetinyurek-Yavuz, John W Sijben, Arend Heerschap, Marcel G M Olde Rikkert
BACKGROUND: Synaptic dysfunction contributes to cognitive impairment in Alzheimer's disease and may be countered by increased intake of nutrients that target brain phospholipid metabolism. In this study, we explored whether the medical food Souvenaid affects brain phospholipid metabolism in patients with Alzheimer's disease. METHODS: Thirty-four drug-naive patients with mild Alzheimer's disease (Mini Mental State Examination score ≥20) were enrolled in this exploratory, double-blind, randomized controlled study...
July 26, 2017: Alzheimer's Research & Therapy
https://www.readbyqxmd.com/read/28744962/inverse-estimation-of-cardiac-activation-times-via-gradient-based-optimisation
#16
Siri Kallhovd, Mary M Maleckar, Marie E Rognes
Computational modeling may provide a quantitative framework for integrating multi-scale data to gain insight into mechanisms of heart disease, identify and test pharmacological and electrical therapy and interventions, and support clinical decisions. Patient-specific computational cardiac models can help guide such procedures, and cardiac inverse modelling is a promising alternative to adequately personalize these models. Indeed, full cardiac inverse modelling is currently becoming computationally feasible; however, fundamental work to assess the feasibility of emerging techniques is still needed...
July 25, 2017: International Journal for Numerical Methods in Biomedical Engineering
https://www.readbyqxmd.com/read/28744093/origins-of-the-phototransduction-delay-as-inferred-from-stochastic-and-deterministic-simulation-of-the-amplification-cascade
#17
Alexander Yu Rotov, Luba A Astakhova, Michael L Firsov, Victor I Govardovskii
PURPOSE: To identify steps of the phototransduction cascade responsible for the delay of the photoresponse. METHODS: Electrical responses of fish (Carassius) cones and Rana ridibunda frog rods and cones were recorded with a suction pipette technique and as an aspartate-isolated mass receptor potential from isolated perfused retinas. Special attention was paid to sufficiently high temporal resolution (1-ms flash, 700 Hz amplification bandpass). Stochastic simulation of the activation steps from photon absorption to the formation of catalytically active phosphodiesterase (PDE) was performed...
2017: Molecular Vision
https://www.readbyqxmd.com/read/28743736/sfpq-a-multifunctional-nuclear-protein-regulates-the-transcription-of-pde3a
#18
Dong Keun Rhee, Steven C Hockman, Sun-Kyung Choi, Yong-Eun Kim, Chungoo Park, Vincent C Manganiello, Kee Kwang Kim
Phosphodiesterase 3A (PDE3A), a member of the cGMP-inhibited cyclic nucleotide phosphodiesterase (PDE) family, plays important roles in oocyte maturation and vascular smooth muscle cell proliferation. However, the molecular mechanisms that regulate PDE3A gene expression remain largely unknown. In this study, we investigated the transcriptional regulation of PDE3A , and found that the splicing factor proline and glutamine rich (SFPQ) protein modulated PDE3A mRNA levels. Multiple transcription start sites (TSS1, 2, and 3) were identified within the first exon of PDE3A using 5'-rapid amplification of cDNA ends (RACE)...
July 25, 2017: Bioscience Reports
https://www.readbyqxmd.com/read/28737056/quantification-of-human-brain-pde4-occupancy-by-gsk356278-a-11-c-r-rolipram-pet-study
#19
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
#20
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
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