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Gw-501516

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https://www.readbyqxmd.com/read/23779049/ppar%C3%AE-binding-to-heme-oxygenase-1-promoter-prevents-angiotensin-ii-induced-adipocyte-dysfunction-in-goldblatt-hypertensive-rats
#1
K Sodhi, N Puri, D H Kim, T D Hinds, L A Stechschulte, G Favero, L Rodella, J I Shapiro, D Jude, N G Abraham
OBJECTIVE: Renin-angiotensin system (RAS) regulates adipogenic response with adipocyte hypertrophy by increasing oxidative stress. Recent studies have shown the role of peroxisome proliferator-activated receptor-δ (PPARδ) agonist in attenuation of angiotensin II-induced oxidative stress. The aim of this study was to explore a potential mechanistic link between PPARδ and the cytoprotective enzyme heme oxygenase-1 (HO-1) and to elucidate the contribution of HO-1 to the adipocyte regulatory effects of PPARδ agonism in an animal model of enhanced RAS, the Goldblatt 2 kidney 1 clip (2K1C) model...
March 2014: International Journal of Obesity: Journal of the International Association for the Study of Obesity
https://www.readbyqxmd.com/read/22051054/synthesis-molecular-modeling-studies-and-biological-evaluation-of-fluorine-substituted-analogs-of-gw-501516
#2
Calin C Ciocoiu, Aina W Ravna, Ingebrigt Sylte, Arild C Rustan, Trond Vidar Hansen
(±)-2-Fluoro-2-(2-methyl-4-(((4-methyl-2-(4-(trifluoromethyl)phenyl)thiazol-5-yl)methyl)thio)phenoxy)acetic acid (2a) has been prepared and subjected to biological testing against all three subtypes of the PPARs. This compound exhibited agonist effects with EC(50) values of 560 and 55 nM against PPARα and PPARδ, respectively, in a luciferase assay. Moreover, compound (±)-2a also exhibited potent ability to induce oleic acid oxidation in a human myotube cell assay with EC(50)=3.7 nM. Compound (±)-2a can be classified as a dual PPARα/δ agonist with a 10-fold higher potency against the PPARδ receptor than against the PPARα receptor...
December 1, 2011: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/21215640/effect-of-structurally-constrained-oxime-ether-linker-on-ppar-subtype-selectivity-discovery-of-a-novel-and-potent-series-of-ppar-pan-agonists
#3
Pankaj Makadia, Shailesh R Shah, Harikishore Pingali, Pandurang Zaware, Darshit Patel, Suresh Pola, Baban Thube, Priyanka Priyadarshini, Dinesh Suthar, Maanan Shah, Suresh Giri, Chitrang Trivedi, Mukul Jain, Pankaj Patel, Rajesh Bahekar
A novel series of thaizole and oxazole containing phenoxy acetic acid derivatives is reported as PPAR-pan agonists. Incorporation of structurally constrained oxime-ether based linker in the chemotype of a potent PPARδ selective agonist GW-501516 was adapted as designing strategy. In vitro, selected test compounds 12a, 12c, 17a and 18a showed PPAR-pan agonists activities and among these four compounds tested, 12a emerged as highly potent and efficacious compound, while 17a exhibited moderate and balanced PPAR-pan agonistic activity...
January 15, 2011: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/21113965/synthesis-biological-evaluation-and-molecular-modeling-of-gw-501516-analogues
#4
Calin C Ciocoiu, Aina W Ravna, Ingebrigt Sylte, Trond Vidar Hansen
Eleven analogues of GW 501516 (1) were prepared and subjected to biological testing in a semi-high throughput human skeletal muscle cell assay. The assay testing indicated that all analogues elicited oxidation of oleic acid. Among the most potent agonists, 2e (2-{2-ethyl-4-[(4-methyl-2-(4-trifluoromethylphenyl)thiazol-5-yl)methylthio]phenoxy}-2-methylpropanoic acid), was also subjected to a luciferase-based transfection assay, which showed that this compound is a potent agonist against PPARδ and a moderate agonist against PPARα...
November 2010: Archiv der Pharmazie
https://www.readbyqxmd.com/read/20538899/oral-administration-of-a-ppar-delta-agonist-to-rodents-worsens-not-improves-maximal-insulin-stimulated-glucose-transport-in-skeletal-muscle-of-different-fibers
#5
Justin Cresser, Arend Bonen, Adrian Chabowski, Leslie E Stefanyk, Roberto Gulli, Ian Ritchie, David J Dyck
Agonists targeting the nuclear receptor peroxisome proliferator-activated receptors (PPAR)-delta may be potential therapeutic agents for insulin-resistant related conditions, as they may be able to stimulate fatty acid (FA) oxidation and attenuate the accumulation of harmful lipid species in skeletal muscle. Several reports have demonstrated that PPAR-delta agonists improve whole body insulin sensitivity. However, whether these agonists exert their direct effects on glucose and FA metabolism in skeletal muscle, and specifically with different fiber types, is unknown...
August 2010: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
https://www.readbyqxmd.com/read/20445066/peroxisome-proliferator-activated-receptor-delta-regulation-of-mir-15a-in-ischemia-induced-cerebral-vascular-endothelial-injury
#6
Ke-Jie Yin, Zhen Deng, Milton Hamblin, Yi Xiang, Huarong Huang, Jifeng Zhang, Xiaodan Jiang, Yanzhuang Wang, Y Eugene Chen
Cerebral vascular endothelial cell (CEC) degeneration significantly contributes to blood-brain barrier (BBB) breakdown and neuronal loss after cerebral ischemia. Recently, emerging data suggest that peroxisome proliferator-activated receptor delta (PPARdelta) activation has a potential neuroprotective role in ischemic stroke. Here we report for the first time that PPARdelta is significantly reduced in oxygen-glucose deprivation (OGD)-induced mouse CEC death. Interestingly, PPARdelta overexpression can suppress OGD-induced caspase-3 activity, Golgi fragmentation, and CEC death through an increase of bcl-2 protein levels without change of bcl-2 mRNA levels...
May 5, 2010: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/20403648/synthesis-and-dual-pparalpha-delta-agonist-effects-of-1-4-disubstituted-1-2-3-triazole-analogues-of-gw-501516
#7
Calin C Ciocoiu, Natasa Nikolić, Huyen Hoa Nguyen, G Hege Thoresen, Arne J Aasen, Trond Vidar Hansen
Ten 1,4-disubstituted 1,2,3-triazoles 2a-2j were prepared and tested for their ability to increase oleic acid oxidation in human myotubes using a high-throughput multiwell assay. Compounds 2e (2-{4-[(1-(3-fluoro-4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)methylthio]-2-methylphenoxy}acetic acid) and 2i (2-{4-[(1-(3-chloro-4-(trifluoromethoxy)phenyl)-1H-1,2,3-triazol-4-yl)methylthio]-2-methylphenoxy}acetic acid) exhibited potent agonist activities. Compounds 2e and 2i also exhibited powerful agonist effects for both PPARalpha and PPARdelta in a luciferase-based assay...
July 2010: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/19483413/-design-and-synthesis-of-peroxisome-proliferator-activated-receptor-ppar-delta-agonists-and-its-implication-to-the-driving-force-to-elicit-ppar-delta-selectivity
#8
REVIEW
Jun-Ichi Kasuga, Takuji Oyama, Izumi Nakagome, Atsushi Aoyama, Kumiko Sako, Makoto Makishima, Shuichi Hirono, Kosuke Morikawa, Yuichi Hashimoto, Hiroyuki Miyachi
A series of 3-(4-alkoxypheny)propanoic acid derivatives was prepared as candidate peroxisome proliferator-activated receptor (PPAR) delta-selective agonists, based on our previously discovered potent human PPARalpha/delta dual agonist TIPP-401 as a lead compound. Structure-activity relationship studies clearly indicated the importance of the chain length of the alkoxy group at the 4-position, and the n-butoxy compound exhibited the most potent PPARdelta transactivation activity and highest PPARdelta selectivity...
June 2009: Yakugaku Zasshi: Journal of the Pharmaceutical Society of Japan
https://www.readbyqxmd.com/read/19422681/effects-of-the-ppar-beta-agonist-gw501516-in-an-in-vitro-model-of-brain-inflammation-and-antibody-induced-demyelination
#9
Antoinette Defaux, Marie-Gabrielle Zurich, Olivier Braissant, Paul Honegger, Florianne Monnet-Tschudi
BACKGROUND: Brain inflammation plays a central role in numerous brain pathologies, including multiple sclerosis (MS). Microglial cells and astrocytes are the effector cells of neuroinflammation. They can be activated also by agents such as interferon-gamma (IFN-gamma) and lipopolysaccharide (LPS). Peroxisome proliferator-associated receptor (PPAR) pathways are involved in the control of the inflammatory processes, and PPAR-beta seems to play an important role in the regulation of central inflammation...
2009: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/18047848/lipids-lipoproteins-and-peroxisome-proliferator-activated-receptor-delta
#10
REVIEW
Dennis L Sprecher
Peroxisome proliferator activated receptors (PPARs) are nuclear receptors activated by small, lipophilic compounds. Typically resident on nuclear DNA, full activation requires heterodimer formation with retinoid X receptor and ligand binding, leading to modulation in the expression of hundreds of genes. Of the 3 described forms, (PPAR-alpha, PPAR-gamma, and PPAR-delta), PPAR-delta has been the least investigated. Preclinical in vitro data show that activation of PPAR-delta, like PPAR-alpha, results in enhancement of fatty acid oxidation, leading to increased energy production in the form of adenosine triphosphate and of energy uncoupling...
December 3, 2007: American Journal of Cardiology
https://www.readbyqxmd.com/read/17532641/design-synthesis-and-evaluation-of-potent-structurally-novel-peroxisome-proliferator-activated-receptor-ppar-delta-selective-agonists
#11
Jun-Ichi Kasuga, Izumi Nakagome, Atsushi Aoyama, Kumiko Sako, Michiyasu Ishizawa, Michitaka Ogura, Makoto Makishima, Shuichi Hirono, Yuichi Hashimoto, Hiroyuki Miyachi
A series of 3-(4-alkoxyphenyl)propanoic acid derivatives was prepared as candidate peroxisome proliferator-activated receptor (PPAR) delta-selective agonists, based on our previously discovered potent human PPARalpha/delta dual agonist TIPP-401 as a lead compound. Structure-activity relationship studies clearly indicated the importance of the chain length of the alkoxy group at the 4-position, and the n-butoxy compound exhibited the most potent PPARdelta transactivation activity and highest PPARdelta selectivity...
August 1, 2007: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/17193275/-4-2h-1-2-3-benzotriazol-2-yl-phenoxy-alkanoic-acids-as-agonists-of-peroxisome-proliferator-activated-receptors-ppars
#12
COMPARATIVE STUDY
Anna Sparatore, Cristina Godio, Elena Perrino, Sergio Romeo, Bart Staels, Jean-Charles Fruchart, Maurizio Crestani
A series of [4-(2H-1,2,3-benzotriazol-2-yl)phenoxy]alkanoic acids has been synthesized and tested as agonists of Peroxisome Proliferator-Activated Receptor (PPAR) alpha, gamma, and delta. Three compounds displayed 56 to 96% of maximal activity of the reference drug Wy-14643 on PPARalpha, and two of these, i.e., 1 and 5, exhibited also moderate activity on either PPARgamma or delta with efficacy equal to 50% and 46% of that of rosiglitazone and GW 501516, respectively. Thus, compounds 1 and 5 represent interesting starting point for preparing novel agents for the treatment of dyslipidemia or of dyslipidemic type-2 diabetes...
April 2006: Chemistry & Biodiversity
https://www.readbyqxmd.com/read/16801985/gateways-to-clinical-trials
#13
M Bayés, X Rabasseda, J R Prous
Gateways to Clinical Trials are a guide to the most recent clinical trials in current literature and congresses. The data in the following tables have been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com/. This issue focuses on the following selection of drugs: Adalimumab, adenosine triphosphate, alemtuzumab, alendronate sodium/cholecalciferol, aliskiren fumarate, AMGN-0007, aminolevulinic acid methyl ester, anakinra, anidulafungin, aripiprazole, atomoxetine hydrochloride; Bevacizumab, bosentan; Calcipotriol/beta methasone dipropionate, caldaret hydrate, caspofungin acetate, cetuximab, cinacalcet hydrochloride, clopidogrel, cocaine-BSA conjugate, conivaptan hydrochloride, Cypher; Darbepoetin alfa, delmitide, desloratadine, desmoteplase, desoxyepothilone B, disufenton sodium, DU-176b, duloxetine hydrochloride, dutasteride; EBV-specific CTLs, ecogramostim, edodekin alfa, efalizumab, eletriptan, emtricitabine, entecavir, erlotinib hydrochloride, ertapenem sodium, escitalopram oxalate, etoricoxib, everolimus, ezetimibe; Fanapanel, fondaparinux sodium; Gefitinib, GTI-2040, GW-501516; Her2 E75-peptide vaccine, human insulin; Ibogaine, icatibant acetate, Id-KLH vaccine, imatinib mesylate, immune globulin subcutaneous [human], indacaterol, inolimomab, ipilimumab, i...
May 2006: Methods and Findings in Experimental and Clinical Pharmacology
https://www.readbyqxmd.com/read/16625823/gw-501516-glaxosmithkline-ligand
#14
REVIEW
Patricia Pelton
GlaxoSmithKline and Ligand are developing GW-501516, a peroxisome proliferator-activator receptor-delta agonist for the potential treatment of dyslipidemia. Phase II clinical trials of this compound are ongoing.
April 2006: Current Opinion in Investigational Drugs
https://www.readbyqxmd.com/read/16278250/ppardelta-activator-gw-501516-has-no-acute-effect-on-glucose-transport-in-skeletal-muscle
#15
Shin Terada, Scott Wicke, John O Holloszy, Dong-Ho Han
It has been reported that treatment of cultured human skeletal muscle myotubes with the peroxisome proliferator-activated receptor-delta (PPARdelta) activator GW-501516 directly stimulates glucose transport and enhances insulin action. Cultured myotubes are minimally responsive to insulin stimulation of glucose transport and are not a good model for studying skeletal muscle glucose transport. The purpose of this study was to evaluate the effect of GW-501516 on glucose transport to determine whether the findings on cultured myotubes have relevance to skeletal muscle...
April 2006: American Journal of Physiology. Endocrinology and Metabolism
https://www.readbyqxmd.com/read/16239165/statins-and-pparalpha-agonists-induce-myotoxicity-in-differentiated-rat-skeletal-muscle-cultures-but-do-not-exhibit-synergy-with-co-treatment
#16
COMPARATIVE STUDY
Timothy E Johnson, Xiaohua Zhang, Shu Shi, Diane R Umbenhauer
Statins and fibrates (weak PPARalpha agonists) are prescribed for the treatment of lipid disorders. Both drugs cause myopathy, but with a low incidence, 0.1-0.5%. However, combined statin and fibrate therapy can enhance myopathy risk. We tested the myotoxic potential of PPAR subtype selective agonists alone and in combination with statins in a differentiated rat myotube model. A pharmacologically potent experimental PPARalpha agonist, Compound A, induced myotoxicity as assessed by TUNEL staining at a minimum concentration of 1 nM, while other weaker PPARalpha compounds, for example, WY-14643, Gemfibrozil and Bezafibrate increased the percentage of TUNEL-positive nuclei at micromolar concentrations...
November 1, 2005: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/16187688/cardiovascular-disease-and-ppardelta-targeting-the-risk-factors
#17
REVIEW
George E O Muscat, Uwe Dressel
Metabolism, in part, is regulated by the peroxisome proliferator-activated receptors (PPARs). The PPARs act as nutritional lipid sensors and three mammalian PPAR subtypes designated PPARalpha (NR1C1), PPARgamma (NR1C3) and PPARdelta (NR1C2) have been identified. This subgroup of nuclear hormone receptors binds DNA and controls gene expression at the nexus of pathways that regulate lipid and glucose homeostasis, energy storage and expenditure in an organ-specific manner. Recent evidence has demonstrated activation of PPARdelta in the major mass peripheral tissue (ie, adipose and skeletal muscle)...
September 2005: Current Opinion in Investigational Drugs
https://www.readbyqxmd.com/read/15834459/gateways-to-clinical-trials
#18
M Bayés, X Rabasseda, J R Prous
Gateways to Clinical Trials is a guide to the most recent clinical trials reported in current literature and congresses. The data in the following tables have been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs:[188Re]-HDD; A-179578, adalimumab, AK-602, albumin interferon alfa, alfimeprase, amelubant, anakinra, anti-CD2 MAb, APD-356, aripiprazole, atvogen; Bimatoprost, bimosiamose, BLP-25, brivaracetam; Caspofungin acetate, cilansetron, CMV vaccine (bivalent), conivaptan hydrochloride, Cypher; Darbepoetin alfa, darifenacin hydrobromide, D-D4FC, decitabine, dnaJP1, doranidazole, dronedarone hydrochloride; Efalizumab, efaproxiral sodium, emtricitabine, Endeavor, entecavir, erlotinib hydrochloride, escitalopram oxalate, etoricoxib, etravirine, ezetimibe; Fampridine, fenretinide, ferumoxtran-10, forodesine hydrochloride; Gantacurium chloride, gemi-floxacin mesilate, Glyminox, GW-501516; HBV-ISS, hepavir B, human insulin, HuMax-CD20, hyaluronic acid, HyCAMP; Icatibant, IDEA-070, IGN-311, imatinib mesylate, insulin detemir, insulin glargine, insulin glulisine; Lapatinib, lasofoxifene tartrate, LB-80380, liarozole fumarate, liposome encapsulated doxorubicin, lumiracoxib, LY-570310; MC-1, melatonin, merimepodib, metanicotine, midostaurin; Natalizumab, nicotine conjugate vaccine, NYVAC-HIV C; Patupilone, peginterferon alfa-2a, peginterferon alfa-2b, peginterferon alfa-2b/ribavirin, pelitinib, Peru-15, pexelizumab, PHP, pimecrolimus, prednisolone sodium metasulfobenzoate; Recombinant alfa1-antitrypsin (AAT), retigabine, rHA influenza vaccine, rifalazil, rofecoxib, rosiglitazone maleate/Metformin hydrochloride, rostaporfin, rosuvastatin calcium, rubitecan; Selenite sodium, semilente insulin, SMP-797, sorafenib; Talampanel, tenofovir disoproxil fumarate, TER-199, tiotropium bromide, torcetrapib, treprostinil sodium, TTA; ValboroPro, valdecoxib, val-mCyd, valtorcitabine dihydrochloride: XP-828L...
January 2005: Methods and Findings in Experimental and Clinical Pharmacology
https://www.readbyqxmd.com/read/15764152/peroxisome-proliferator-activated-receptor-expression-and-activation-in-normal-human-colonic-epithelial-cells-and-tubular-adenomas
#19
Mads Wichmann Matthiessen, Gitte Pedersen, Tatjana Albrektsen, Sven Adamsen, Jan Fleckner, Jørn Brynskov
OBJECTIVE: Peroxisome proliferator-activated receptor (PPAR) ligands, widely used in type 2 diabetes treatment, have variably been shown to promote or prevent colon tumor formation in animal models and cell lines, but their role in normal human colon is unknown. The aim of this study was to determine PPAR expression and function in normal human colonic epithelial cells and tubular adenomas. MATERIAL AND METHODS: Short-term cultures of normal human colonic epithelial cells were established from biopsies obtained in 42 patients with normal colonoscopy...
February 2005: Scandinavian Journal of Gastroenterology
https://www.readbyqxmd.com/read/15751073/rosiglitazone-induces-interleukin-1-receptor-antagonist-in-interleukin-1beta-stimulated-rat-synovial-fibroblasts-via-a-peroxisome-proliferator-activated-receptor-beta-delta-dependent-mechanism
#20
David Moulin, Arnaud Bianchi, Sandrine Boyault, Sylvie Sebillaud, Meriem Koufany, Mathias Francois, Patrick Netter, Jean-Yves Jouzeau, Bernard Terlain
OBJECTIVE: To study the potency of 2 peroxisome proliferator-activated receptor gamma (PPARgamma) agonists, 15-deoxy-Delta(12,14)-prostaglandin J(2) (15-deoxy-PGJ(2)) and rosiglitazone, to modulate the expression of interleukin-1 receptor antagonist (IL-1Ra) in rat synovial fibroblasts. METHODS: Levels of messenger RNA for IL-1Ra and PPAR isotypes (alpha, beta/delta, gamma) were assessed by real-time polymerase chain reaction in rat synovial fibroblasts exposed to 10 ng/ml of IL-1beta...
March 2005: Arthritis and Rheumatism
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