DOCSLIB.ORG

New Directions with Non-Steroidal Scaffolds

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
New Directions with Non-Steroidal Scaffolds JPT-06776; No of Pages 14 Pharmacology & Therapeutics xxx (2015) xxx–xxx Contents lists available at ScienceDirect Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/pharmthera Selective glucocorticoid receptor modulation: New directions with non-steroidal scaffolds Nora Sundahl a, Jolien Bridelance a,1, Claude Libert b,c, Karolien De Bosscher d,⁎,2, Ilse M. Beck a,2 a Laboratory of Experimental Cancer Research (LECR), Department of Radiation Oncology & Experimental Cancer Research, Ghent University, Gent, Belgium b Department for Molecular Biomedical Research, VIB, Gent, Belgium c Department of Biomedical Molecular Biology, Ghent University, Gent, Belgium d Receptor Research Laboratories, Nuclear Receptor Lab (NRL), VIB Department of Medical Protein Research, Ghent University, Gent, Belgium article info abstract Keywords: Glucocorticoids remain the frontline treatment for inflammatory disorders, yet represent a double-edged sword Glucocorticoids with beneficial therapeutic actions alongside adverse effects, mainly in metabolic regulation. Considerable efforts Glucocorticoid receptor were made to improve this balance by attempting to amplify therapeutic beneficial anti-inflammatory actions Selective glucocorticoid receptor modulator and to minimize adverse metabolic actions. Most attention has focused on the development of novel compounds Compound A favoring the transrepressing actions of the glucocorticoid receptor, assumed to be important for anti- Side effects inflammatory actions, over the transactivating actions, assumed to underpin the undesirable actions. These Glucocorticoid resistance compounds are classified as selective glucocorticoid receptor agonists (SEGRAs) or selective glucocorticoid receptor modulators (SEGRMs). The latter class is able to modulate the activity of a GR agonist and/or may not classically bind the glucocorticoid receptor ligand-binding pocket. SEGRAs and SEGRMs are collectively denominated SEGRAMs (selective glucocorticoid receptor agonists and modulators). Although this transrepression vs transactivation concept proved to be too simplistic, the developed SEGRAMs were helpful in elucidating various molecular actions of the glucocorticoid receptor, but have also raised many novel questions. We discuss lessons learned from recent mechanistic studies of selective glucocorticoid receptor modulators. This is approached by analyzing recent experimental insights in comparison with knowledge obtained using mutant GR research, thus clarifying the current view on the SEGRAM field. These insights also contribute to our under- standing of the processes controlling glucocorticoid-mediated side effects as well as glucocorticoid resistance. Our perspective on non-steroidal SEGRAs and SEGRMs considers remaining opportunities to address research gaps in order to harness the potential for more safe and effective glucocorticoid receptor therapies. © 2015 Published by Elsevier Inc. Contents 1. Introduction................................................ 0 2. Review:Glucocorticoid-vsSEGRAM-mediatedGRsignaling.......................... 0 3. Conclusions................................................ 0 Conflictofintereststatement.......................................... 0 Roleofthefundingsource............................................ 0 Acknowledgments............................................... 0 AppendixA. Supplementarydata....................................... 0 References................................................... 0 Abbreviations:AP-1, activatorprotein 1;CpdA,CompoundA;CRH,corticotropin-releasinghormone;DBD,DNAbinding domain;DUSP,dualspecificityphosphatase;ENaC,epithelialNa+ channels; GC,glucocorticoid; GILZ, glucocorticoid induced leucine zipper; GR, glucocorticoidreceptor; GRE, glucocorticoid-responsive element; HSP, heat shockprotein;LBD, ligand-binding domain;MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor κB; nGRE, negative glucocorticoidresponsive element; OPG, osteoprotegerin; SEGRA, selective glucocorticoid recep- tor agonist; SEGRM, selective glucocorticoid receptor modulator; SEGRAM, selective glucocorticoid receptor agonist and modulator. ⁎ Corresponding author at: Receptor Research Laboratories, Nuclear Receptor Lab (NRL), VIB Department of Medical Protein Research, VIB, UGent, Albert Baertsoenkaai 3, B-9000 Gent, Belgium. Tel.: +32 92649363; fax: +32 26499490. E-mail address: [email protected] (K. De Bosscher). 1 Moved to Molecular Signaling and Cell Death, VIB Inflammation Research center, Ghent University, Gent, Belgium. 2 Shared senior authorship. http://dx.doi.org/10.1016/j.pharmthera.2015.05.001 0163-7258/© 2015 Published by Elsevier Inc. Please cite this article as: Sundahl, N., et al., Selective glucocorticoid receptor modulation: New directions with non-steroidal scaffolds, Pharma- cology & Therapeutics (2015), http://dx.doi.org/10.1016/j.pharmthera.2015.05.001 2 N. Sundahl et al. / Pharmacology & Therapeutics xxx (2015) xxx–xxx 1. Introduction shock and various blood cancers (e.g. multiple myeloma); they are also used for preventing rejection after transplant, and for correcting ad- 1.1. Glucocorticoids renal cortical hormone insufficiency. The clinical success of exogenous GCs (e.g. dexamethasone, prednisolone…) is largely due to their anti- Glucocorticoids (GCs) are steroid hormones produced in the adrenal inflammatory characteristics. GCs suppress inflammation mainly via cortex on a circadian rhythm. The production of these hormones is reg- transrepression of inflammatory and immune genes, such as genes cod- ulated by the hypothalamic-pituitary-adrenal axis. Neural, endocrine ing for cytokines, chemokines, inflammatory enzymes and receptors, and also cytokine signals converge at the hypothalamus periventricular and adhesion molecules that play a role in migration of cells towards nucleus. These signals determine the secretion of corticotropin- sites of inflammation (Belvisi, 2004; Ito et al., 2006b; McMaster & Ray, releasing hormone (CRH) from the hypothalamus into the portal system 2008; Barnes, 2011). Unfortunately, the use of GCs is often not recom- of the pituitary gland. Successively, the CRH induces secretion of adreno- mended, due to the wide range of side effects. These include diabetes, corticotropic hormone (ACTH) from the anterior pituitary, which in turn muscle wasting and osteoporosis (Schacke et al., 2002). stimulates synthesis and secretion of the glucocorticoid cortisol (also The current challenge is to minimize as many as possible of these named hydrocortisone) from the zona fasciculata of the adrenal cortex. side effects and optimize GR-associated beneficial effects. The idea of Feedback mechanisms ensure a tight control on the cortisol production resolving all the side effects associated with glucocorticoids is, however, and release (Fig. 1). Approximately 10% of the secreted cortisol is free a utopia. It would therefore already be a great achievement to eliminate and thereby active; the other 90% is bound to systemic corticosteroid- the clinically most burdening ones. Recent research has intensely fo- binding globulins (Chapman et al., 2013; Nicolaides et al., 2014). cused on a class of pharmacologic compounds, selective glucocorticoid GCs activate the glucocorticoid receptor (GR), a transcription factor receptor agonists and modulators (SEGRAMs), that display an improved belonging to the nuclear receptor superfamily (see Section 2.1). therapeutic index in vivo via a select skewing of the GR effector profile (Rosen & Miner, 2005). The current SEGRAMs only (or mainly) work 1.1.1. Therapeutic use of glucocorticoids via the transrepression pathway of glucocorticoid receptors (GRs), GCs are widely used for the treatment of inflammatory, immune and thereby resulting in a more specific action radius of GR (McMaster & allergic disorders (e.g. rheumatoid arthritis, asthma), brain edema, Ray, 2008; De Bosscher, 2010; De Bosscher et al., 2010b). 1.2. Selective glucocorticoid receptor modulators It is assumed that the anti-inflammatory effects of GCs are largely due to GR transrepression mechanisms, while GR transactivation is ac- countable for the greater part of GC treatment-associated side effects. This statement has, however, turned out to be too simplistic. It has indeed been shown that some side effects are predominantly mediated via transactivation (e.g. hyperglycemia and muscle wasting), yet other side effects arise from transrepression (e.g. hypothalamic-pituitary- adrenal axis suppression), and still other side effects (e.g. osteoporosis) are mediated by both transactivation and transrepression (Schacke et al., 2002; Carballo-Jane et al., 2004). Nevertheless, examples of GR ligands exist, which can selectively induce transrepression without significant transactivation, and for which in the long run the risk of systemic side effects may be reduced, while anti-inflammatory activities are maintained. Compounds that can activate specific GR mechanisms and thus alter GR-mediated gene expression profiles are referred to as dissociated compounds, selective glucocorticoid receptor agonists (SEGRAs) or modulators (SEGRMs) (Rosen & Miner, 2005; Beck et al., 2009) (Fig. 2). The term SEGRA was the first term used, as the compounds historically were derived from a steroidal scaffold (e.g. RU 24858) and they often still exhibited a partial agonistic effect on the transactivation mechanism of GR (Belvisi et al., 2001). The use of the term ‘SEGRM’ was initiated to distance the newer, non-steroidal compounds from the older ones. One of the first
Load more

Recommended publications
  • Classification Decisions Taken by the Harmonized System Committee from the 47Th to 60Th Sessions (2011
    CLASSIFICATION DECISIONS TAKEN BY THE HARMONIZED SYSTEM COMMITTEE FROM THE 47TH TO 60TH SESSIONS (2011 - 2018) WORLD CUSTOMS ORGANIZATION Rue du Marché 30 B-1210 Brussels Belgium November 2011 Copyright © 2011 World Customs Organization. All rights reserved. Requests and inquiries concerning translation, reproduction and adaptation rights should be addressed to [email protected]. D/2011/0448/25 The following list contains the classification decisions (other than those subject to a reservation) taken by the Harmonized System Committee ( 47th Session – March 2011) on specific products, together with their related Harmonized System code numbers and, in certain cases, the classification rationale. Advice Parties seeking to import or export merchandise covered by a decision are advised to verify the implementation of the decision by the importing or exporting country, as the case may be. HS codes Classification No Product description Classification considered rationale 1. Preparation, in the form of a powder, consisting of 92 % sugar, 6 % 2106.90 GRIs 1 and 6 black currant powder, anticaking agent, citric acid and black currant flavouring, put up for retail sale in 32-gram sachets, intended to be consumed as a beverage after mixing with hot water. 2. Vanutide cridificar (INN List 100). 3002.20 3. Certain INN products. Chapters 28, 29 (See “INN List 101” at the end of this publication.) and 30 4. Certain INN products. Chapters 13, 29 (See “INN List 102” at the end of this publication.) and 30 5. Certain INN products. Chapters 28, 29, (See “INN List 103” at the end of this publication.) 30, 35 and 39 6. Re-classification of INN products.
    [Show full text]
  • Evidence Review H: Glucocorticoids
    National Institute for Health and Care Excellence Final Rheumatoid arthritis in adults: diagnosis and management Evidence review H Glucocorticoids NICE guideline NG100 Evidence review July 2018 Final This evidence review was developed by the National Guideline Centre Rheumatoid arthritis: Final Contents Disclaimer The recommendations in this guideline represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, professionals are expected to take this guideline fully into account, alongside the individual needs, preferences and values of their patients or service users. The recommendations in this guideline are not mandatory and the guideline does not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and, where appropriate, their carer or guardian. Local commissioners and providers have a responsibility to enable the guideline to be applied when individual health professionals and their patients or service users wish to use it. They should do so in the context of local and national priorities for funding and developing services, and in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Nothing in this guideline should be interpreted in a way that would be inconsistent with compliance with those duties. NICE guidelines cover health and care in England. Decisions on how they apply in other UK countries are made by ministers in the Welsh Government, Scottish Government, and Northern Ireland Executive. All NICE guidance is subject to regular review and may be updated or withdrawn.
    [Show full text]
  • (INN) for Pharmaceutical Substances" WHO/EMP/RHT/TSN/2018.1
    INN Working Document 20.484 13/07/2020 Addendum1 to "The use of stems in the selection of International Nonproprietary names (INN) for pharmaceutical substances" WHO/EMP/RHT/TSN/2018.1 Programme on International Nonproprietary Names (INN) Medicines and Health Products World Health Organization, Geneva © World Health Organization 2020 - All rights reserved. The contents of this document may not be reviewed, abstracted, quoted, referenced, reproduced, transmitted, distributed, translated or adapted, in part or in whole, in any form or by any means, without explicit prior authorization of the WHO INN Programme. This document contains the collective views of the INN Expert Group and does not necessarily represent the decisions or the stated policy of the World Health Organization. Addendum1 to "The use of stem s in the selection of International Nonproprietary Names (INN) for pharmaceutical substances" - WHO/EMP/RHT/TSN/2018.1 1 This addendum is a cumulative list of all new stems selected by the INN Expert Group since the publication of "The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances" 2018. -adenant adenosine receptors antagonists ciforadenant (118), preladenant (99), taminadenant (120), tozadenant (106), vipadenant (103) -caftor cystic fibrosis transmembrane regulator (CFTR) protein modulators, correctors, and amplifiers bamocaftor (121), deutivacaftor (118), elexacaftor (121), galicaftor (119), icenticaftor (122), ivacaftor (104), lumacaftor (105), navocaftor (121), nesolicaftor
    [Show full text]
  • Stembook 2018.Pdf
    The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances FORMER DOCUMENT NUMBER: WHO/PHARM S/NOM 15 WHO/EMP/RHT/TSN/2018.1 © World Health Organization 2018 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition”. Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the World Intellectual Property Organization. Suggested citation. The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances. Geneva: World Health Organization; 2018 (WHO/EMP/RHT/TSN/2018.1). Licence: CC BY-NC-SA 3.0 IGO. Cataloguing-in-Publication (CIP) data.
    [Show full text]
  • A Abacavir Abacavirum Abakaviiri Abagovomab Abagovomabum
    A abacavir abacavirum abakaviiri abagovomab abagovomabum abagovomabi abamectin abamectinum abamektiini abametapir abametapirum abametapiiri abanoquil abanoquilum abanokiili abaperidone abaperidonum abaperidoni abarelix abarelixum abareliksi abatacept abataceptum abatasepti abciximab abciximabum absiksimabi abecarnil abecarnilum abekarniili abediterol abediterolum abediteroli abetimus abetimusum abetimuusi abexinostat abexinostatum abeksinostaatti abicipar pegol abiciparum pegolum abisipaaripegoli abiraterone abirateronum abirateroni abitesartan abitesartanum abitesartaani ablukast ablukastum ablukasti abrilumab abrilumabum abrilumabi abrineurin abrineurinum abrineuriini abunidazol abunidazolum abunidatsoli acadesine acadesinum akadesiini acamprosate acamprosatum akamprosaatti acarbose acarbosum akarboosi acebrochol acebrocholum asebrokoli aceburic acid acidum aceburicum asebuurihappo acebutolol acebutololum asebutololi acecainide acecainidum asekainidi acecarbromal acecarbromalum asekarbromaali aceclidine aceclidinum aseklidiini aceclofenac aceclofenacum aseklofenaakki acedapsone acedapsonum asedapsoni acediasulfone sodium acediasulfonum natricum asediasulfoninatrium acefluranol acefluranolum asefluranoli acefurtiamine acefurtiaminum asefurtiamiini acefylline clofibrol acefyllinum clofibrolum asefylliiniklofibroli acefylline piperazine acefyllinum piperazinum asefylliinipiperatsiini aceglatone aceglatonum aseglatoni aceglutamide aceglutamidum aseglutamidi acemannan acemannanum asemannaani acemetacin acemetacinum asemetasiini aceneuramic
    [Show full text]
  • A General Introduction to Glucocorticoid Biology
    REVIEW published: 04 July 2019 doi: 10.3389/fimmu.2019.01545 A General Introduction to Glucocorticoid Biology Steven Timmermans 1,2†, Jolien Souffriau 1,2† and Claude Libert 1,2* 1 Center for Inflammation Research, VIB, Ghent, Belgium, 2 Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium Glucocorticoids (GCs) are steroid hormones widely used for the treatment of inflammation, autoimmune diseases, and cancer. To exert their broad physiological and therapeutic effects, GCs bind to the GC receptor (GR) which belongs to the nuclear receptor superfamily of transcription factors. Despite their success, GCs are hindered by the occurrence of side effects and glucocorticoid resistance (GCR). Increased knowledge on GC and GR biology together with a better understanding of the molecular mechanisms underlying the GC side effects and GCR are necessary for improved GC therapy development. We here provide a general overview on the current insights in GC biology with a focus on GC synthesis, regulation and physiology, role in inflammation inhibition, and on GR function and plasticity. Furthermore, novel and selective therapeutic strategies are proposed based on recently recognized distinct molecular mechanisms of Edited by: the GR. We will explain the SEDIGRAM concept, which was launched based on our Miriam Wittmann, University of Leeds, United Kingdom research results. Reviewed by: Keywords: glucocorticoids, glucocorticoid receptor, inflammation, molecular biology, SEDIGRAM Carlo Riccardi, University of Perugia, Italy Nicolas C. Nicolaides, DISCOVERY OF GLUCOCORTICOIDS AND THE “Aghia Sophia” Children’s GLUCOCORTICOID RECEPTOR Hospital, Greece *Correspondence: The first steps leading to the discovery of glucocorticoids (GCs) took place in the 19th century when Claude Libert the physician Thomas Addison described that patients suffering from (chronic) fatigue, muscular [email protected] degeneration, weight loss, and a strange darkening of the skin could obtain beneficial effects from †These authors have contributed adrenal extracts (1).
    [Show full text]
  • University of Birmingham Therapeutic
    University of Birmingham Therapeutic glucocorticoids mechanisms of actions in rheumatic diseases Raza, Karim; Hardy, Rowan; Cooper, Mark S. DOI: 10.1038/s41584-020-0371-y https://www.nature.com/articles/s41584-020-0371-y#article-info License: Other (please specify with Rights Statement) Document Version Peer reviewed version Citation for published version (Harvard): Raza, K, Hardy, R & Cooper, MS 2020, 'Therapeutic glucocorticoids mechanisms of actions in rheumatic diseases', Nature Reviews Rheumatology, vol. 16, no. 3, pp. 133-144. https://doi.org/10.1038/s41584-020-0371- y, https://doi.org/https://www.nature.com/articles/s41584-020-0371-y#article-info Link to publication on Research at Birmingham portal Publisher Rights Statement: Subject to Springer Nature re-use terms: https://www.nature.com/nature-research/editorial-policies/self-archiving-and-license-to- publish#terms-for-use General rights Unless a licence is specified above, all rights (including copyright and moral rights) in this document are retained by the authors and/or the copyright holders. The express permission of the copyright holder must be obtained for any use of this material other than for purposes permitted by law. •Users may freely distribute the URL that is used to identify this publication. •Users may download and/or print one copy of the publication from the University of Birmingham research portal for the purpose of private study or non-commercial research. •User may use extracts from the document in line with the concept of ‘fair dealing’ under the Copyright, Designs and Patents Act 1988 (?) •Users may not further distribute the material nor use it for the purposes of commercial gain.
    [Show full text]
  • Inflammation/Immunology
    Inflammation/Immunology The diseases caused by disorders of the immune system fall into two broad categories: immunodeficiency and autoimmunity. Immunotherapy is also often used in the immunosuppressed (such as HIV patients) and people suffering from other immune deficiencies or autoimmune diseases. This includes regulating factors such as IL-2, IL-10, IFN-α. Infection with HIV is characterized not only by development of profound immunodeficiency but also by sustained inflammation and immune activation. Chronic inflammation as a critical driver of immune dysfunction, premature appearance of aging-related diseases, and immune deficiency. www.MedChemExpress.com 1 Inflammation/Immunology Inhibitors & Modulators (+)-Borneol (+)-DHMEQ ((1R,2R,6R)-Dehydroxymethylepoxyquinomicin; (d-Borneol) Cat. No.: HY-N1368A (1R,2R,6R)-DHMEQ) Cat. No.: HY-14645A Bioactivity: (+)-Borneol (d-Borneol) is a natural bicyclic monoterpene used Bioactivity: (+)-DHMEQ is an activator of antioxidant transcription factor for analgesia and anesthesia in traditional Chinese medicine; Nrf2. (+)-DHMEQ is the enantiomer of (-)-DHMEQ. (-)-DHMEQ enhances GABA receptor activity with an EC50 of 248 μM. inhibits NF-kB than its enantiomer (+)-DHMEQ. Purity: 98.0% Purity: 98.02% Clinical Data: No Development Reported Clinical Data: No Development Reported Size: 10mM x 1mL in DMSO, Size: 10mM x 1mL in DMSO, 100 mg 2 mg, 5 mg, 10 mg, 25 mg (-)-Epicatechin (-)-Ketoconazole ((-)-Epicatechol; Epicatechin; epi-Catechin) Cat. No.: HY-N0001 Cat. No.: HY-B0105B Bioactivity: (-)-Epicatechin inhibits cyclooxygenase-1 ( COX-1) with an Bioactivity: (-)-Ketoconazole is one of the enantiomer of Ketoconazole. Ketoconazole is a racemic mixture of two enantiomers, IC50 of 3.2 μM. (-)-Epicatechin inhibits the IL-1β-induced expression of iNOS by blocking the nuclear localization of the levoketoconazole ((2S,4R)-(−)-ketoconazole) and p65 subunit of NF-κB.
    [Show full text]
  • Improved Glucocorticoid Receptor Ligands: Fantastic Beasts, but How to Find Them?
    PERSPECTIVE published: 24 September 2020 doi: 10.3389/fendo.2020.559673 Improved Glucocorticoid Receptor Ligands: Fantastic Beasts, but How to Find Them? Laura Van Moortel 1,2,3, Kris Gevaert 2,3 and Karolien De Bosscher 1,2,3* 1 Translational Nuclear Receptor Research (TNRR) Laboratory, VIB, Ghent, Belgium, 2 VIB Center for Medical Biotechnology, VIB, Ghent, Belgium, 3 Department of Biomolecular Medicine, Ghent University, Ghent, Belgium Exogenous glucocorticoids are widely used in the clinic for the treatment of inflammatory disorders and hematological cancers. Unfortunately, their use is associated with debilitating side effects, including hyperglycemia, osteoporosis, mood swings, and weight gain. Despite the continued efforts of pharma as well as academia, the search for so-called selective glucocorticoid receptor modulators (SEGRMs), compounds with strong anti-inflammatory or anti-cancer properties but a reduced number or level of side effects, has had limited success so far. Although monoclonal antibody therapies have Edited by: been successfully introduced for the treatment of certain disorders (such as anti-TNF for Ines Pineda-Torra, University College London, rheumatoid arthritis), glucocorticoids remain the first-in-line option for many other chronic United Kingdom diseases including asthma, multiple sclerosis, and multiple myeloma. This perspective Reviewed by: offers our opinion on why a continued search for SEGRMs remains highly relevant in an Andrew Alt, era where small molecules are sometimes unrightfully considered old-fashioned. Besides University of Michigan, United States Andrew C. B. Cato, a discussion on which bottlenecks and pitfalls might have been overlooked in the past, we Karlsruhe Institute of Technology elaborate on potential solutions and recent developments that may push future research (KIT), Germany in the right direction.
    [Show full text]
  • Androgen Receptor
    DOXORUBICIN HYDROCHLORIDE NICLOSAMIDE TNF-alpha Cellular tumor antigen p53Tubulin FLUOROURACIL DAUNORUBICIN HYDROCHLORIDE Hypoxia-inducible factor 1 alpha PACLITAXEL Tubulin beta chain Tubulin alpha chain TOPOTECAN HYDROCHLORIDE Muscleblind-like protein 1 COLCHICINE DIGOXIN Beta-lactamase AmpCFlap endonuclease 1 Ataxin-2 Paired box protein Pax-8 ORF 73 Anthrax lethal factor DIPHENADIONE 6-phospho-1-fructokinasePODOFILOXVINBLASTINE SULFATE Isocitrate dehydrogenase [NADP] cytoplasmicProtein S100-A4 Huntingtin Signal transducer and activator of transcription 6 DNAThioredoxin polymerase reductase beta14-3-3 1- cytoplasmic protein gamma HSP40- subfamily A- putative Menin/Histone-lysineCruzipain N-methyltransferaseNuclear MLL receptor VINCRISTINEsubfamily 0 group SULFATE B NIFENAZONEmember 1 Sodium/potassium-transporting ATPase AZELASTINEMIDAZOLAM HYDROCHLORIDE HYDROCHLORIDE MITOXANTRONE DIHYDROCHLORIDE Solute carrier organic anion transporter Endonucleasefamily memberBISACODYL 4 4C1 Caspase-1 ATPase family AAA domain-containing protein 5 BreastMETHOTREXATE cancer type 1 susceptibility protein TRIFLURIDINE Sodium/potassium-transporting ATPase alpha-1 chain TRIAMTERENECYTARABINE Transcription factor SKN7 AZACITIDINEDEQUALINIUMTRIFLUPROMAZINE CHLORIDEMothersCLADRIBINE against decapentaplegicEPIRUBICIN homolog HYDROCHLORIDE 3 Pteridine reductase 1 Latent membrane protein 1 MELATONIN Arachidonate 15-lipoxygenase- type II Nuclear receptor coactivator 3 DIGITOXIN Retinoid X receptor alpha AMSACRINE IRINOTECAN HYDROCHLORIDE HYDRATE MEBENDAZOLEBacterial
    [Show full text]
  • Versus Prednisone Or Placebo in Rheumatoid Arthritis: a Randomised, Double-Blind, Multicentre, Phase Iib Study
    Rheumatoid arthritis RMD Open: first published as 10.1136/rmdopen-2018-000889 on 16 April 2019. Downloaded from ORIGINAL ARTICLE Fosdagrocorat (PF-04171327) versus prednisone or placebo in rheumatoid arthritis: a randomised, double-blind, multicentre, phase IIb study Frank Buttgereit, 1 Vibeke Strand,2 Eun Bong Lee,3 Abraham Simon-Campos,4 Dorothy McCabe,5 Astrid Genet,6 Brinda Tammara,7 Ricardo Rojo,8 Judith Hey-Hadavi5 To cite: Buttgereit F, Strand V, ABSTRACT Lee EB, et al. Fosdagrocorat (PF- Objectives Glucocorticoids have anti-inflammatory, Key messages 04171327) versus prednisone transrepression-mediated effects, although adverse events or placebo in rheumatoid (AEs; transactivation-mediated effects) limit long-term use What is already known about this subject? arthritis: a randomised, in patients with rheumatoid arthritis (RA). We evaluated ► Glucocorticoids (GCs) are widely used to treat double-blind, multicentre, patients with rheumatoid arthritis (RA). phase IIb study. RMD Open the efficacy and safety of fosdagrocorat (PF-04171327), a dissociated agonist of the glucocorticoid receptor, versus ► However, they are associated with adverse effects, 2019;5:e000889. doi:10.1136/ and efforts to improve efficacy and reduce adverse rmdopen-2018-000889 prednisone or placebo. Methods In this 12-week, phase II, randomised controlled consequences of GCs include the development of trial, 323 patients with moderate to severe RA were dissociated agonists of the GC receptors (DAGRs). Prepublication history and ► randomised 1:1:1:1:1:1:1 to fosdagrocorat (1 mg, 5 mg, ► Phase I studies of the DAGR, fosdagrocorat additional material for this 10 mg or 15 mg), prednisone (5 mg or 10 mg) or placebo, (10–25 mg), showed equivalent anti-inflammatory paper are available online.
    [Show full text]
  • Anti-Inflammatory Drugs Amy J
    Anti-Inflammatory Drugs Amy J. Rankin Diplomate ACVO Associate Professor Ophthalmology Kansas State University • Corticosteroids • NSAIDs Corticosteroids • Adrenal gland • Glucocorticoids – Zona fasciculata – Zona reticularis – Anti-inflammatory – Metabolic – Immune • Mineralocorticoids – Zona glomerulosa www.news-medical.net – Electrolyte & water balance Riviere & Papich, Veterinary Pharmacology & Therapeutics, 10th Ed Glucocorticoids • Anti-inflammatory – Inhibition of angiogenesis – Reduces leukocyte migration – Decreased capillary permeability – Decreases WBC degranulation • Effects on tissue regeneration – Decreased fibroblastic & collagen formation – Increased collagenolytic activity – Decreased wound healing • Loewenberg et al.,Trends Molec Med, 2007 Loewenberg et al., Trends Molec Med, 2007 Glucocorticoids-Transrepression • GC binds to receptor in cytoplasm • GC-receptor translocates to nucleus • Binds to negative GRE • Down regulation of pro-inflammatory proteins (IL-1 & IL-2) Glucocorticoids-Transrepression • GC binds to receptor in cytoplasm • GC-receptor interacts with transcription factors (TF) NF- ĸβ, AP-1 • GC-receptor complex or TFs do not bind to pro- inflammatory GREs • Down regulation of pro-inflammatory and immune stimulation factors Glucocorticoids-Transrepression • GC binds to receptor in cytoplasm • GC-receptor translocates to the nucleus • GC-receptor binds to nuclear coactivators – AP-1 • Inhibition of pro-inflammatory protein proteins Glucocorticoids-Transactivation Stahn et al., Molecular and Cellular Endocrinology,
    [Show full text]