Anti-Inflammatory Drug Discovery (RSC Drug Discovery, 26) - Hardcover

Hardcover

ISBN 10: 1849734135 ISBN 13: 9781849734134

Verlag: Royal Society of Chemistry, 2012

Inhaltsangabe

Anti-Inflammatory Drug Discovery provides a comprehensive review of recent medicinal chemistry approaches to a variety of important therapeutic targets and provides a key reference for those interested in the prosecution of modern drug discovery programs directed at anti-inflammatory mechanisms of action. The editors, with extensive experience in this field, have selected key thought-leaders who will bring their experience to the medicinal chemistry literature for each target, ranging from components of the arachadonic acid cascade, to kinases, GPCRs, sphingolipids and others, to summarize its background biology and detail new insights, major advances and issues related to bringing new anti-inflammatory therapies to market. Consisting of five main sections key targets covered will include the AA Cascade: mPGES1, cPLA2, Leukotriene A4 Hydrolase, CRTH2; Kinases: P38/PDE4, MAPKAP Kinase 2 (MK2), Syk Kinase Inhibitors, Jak Kinases, IKK , Bruton's Tyrosine Kinase; GPCRs: CCR1, CCR2 Antagonists, CB2 Agonists; Sphingolipids: S1P1 Receptor Agonists, Sphingosine Lyase and Sphingosine Kinase 1 and a final miscellaneous section that looks at Non-Steroidal Dissociated Glucocorticoid Receptor Agonists. The book will be essential reading for pharmacologists, medicinal chemists and pharmaceutical scientists working in industry and academia.

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Professor Laufer has held the chair for Pharmaceutical/Medicinal Chemistry at the University of Tubingen since 1999. He received his Ph.D. from the University of Regensburg (1989) and obtained his Venia Legendi (habilitation) in Pharmaceutical Chemistry from the University of Mainz (1997). From 1990-99 he held senior research and executive positions in pharmaceutical industry. His research interests cover major aspects of anti-inflammatory drug discovery and development, including design, synthesis, biological screening, metabolism, and bioanalytics. The molecular targets that have been the focus of research in his laboratory are the key enzymes of the arachidonate cascade and protein kinases. Two drug candidates from his lab have reached clinical development stages (ML3000-Licofelone, a COX/LOX Inhibitor and CSB3595, a p38 MAPK/PDE4 inhibitor). Professor Laufer has authored 230 publications and is the inventor of 36 patent families. Jeremy I. Levin has been a Director of Medicinal Chemistry for Boehringer-Ingelheim in Ridgefield, Connecticut, since 2010. He received his B.A. from Johns Hopkins University in 1978 and a Ph.D. in organic chemistry with Professor Steven Weinreb at the Pennsylvania State University in 1983. Following a post-doctoral fellowship at the University of California at Irvine with Professor Larry Overman, he spent 25 years in the pharmaceutical industry at American Cyanamid (Lederle laboratories) and Wyeth Research. Dr. Levin has worked in a variety of therapeutic areas including CNS, inflammation and immunology, and oncology. He is the author/co-author of more than 75 papers and an inventor on more than 60 U. S. Patents.

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Anti-Inflammatory Drug Discovery provides a comprehensive review of recent medicinal chemistry approaches to a variety of important therapeutic targets and so provides a key reference for those involved or interested in the prosecution of modern drug discovery programs directed at anti-inflammatory mechanisms of action. The editors, with extensive experience in this field, have selected key thought-leaders who will bring their knowledge to the medicinal chemistry literature based on their own personal experience with each target, ranging from components of the arachadonic acid cascade, to kinases, GPCRs, sphingolipids and others. They summarize the target's background biology and detail new insights, major advances and other issues related to bringing new anti-inflammatory therapies to market. Consisting of five main sections, the key targets covered will include: AA Cascade: mPGES1, cPLA2, Leukotriene A4 Hydrolase, CRTH2 Kinases: P38/PDE4, MAPKAP Kinase 2 (MK2), Syk Kinase Inhibitors, Jak Kinases, IKK, Bruton's Tyrosine Kinase GPCRs: CCR1, CCR2 Antagonists, CB2 Agonists Sphingolipids: S1P1 Receptor Agonists, Sphingosine Lyase and Sphingosine Kinase 1 Miscellaneous: Non-Steroidal Dissociated Glucocorticoid Receptor Agonists. The book will be essential reading for pharmacologists, medicinal chemists and pharmaceutical scientists working in industry and academia.

Auszug. © Genehmigter Nachdruck. Alle Rechte vorbehalten.

Anti-Inflammatory Drug Discovery

By Jeremy I. Levin, Stefan Laufer

The Royal Society of Chemistry

Copyright © 2012 The Royal Society of Chemistry
All rights reserved.

ISBN: 978-1-84973-413-4

Contents

Introduction, 1, 
Section 1: Arachidonic Acid Cascade, 
Chapter 1 Microsomal Prostaglandin E2 Synthase-1 Andreas Koeberle and Oliver Werz, 7, 
Chapter 2 Inhibitors of Cytosolic Phospholipase A2α as Anti-inflammatory Drugs Matthias Lehr, 35, 
Chapter 3 Leukotriene A4 Hydrolase: Biology, Inhibitors and Clinical Applications Cheryl A. Grice, Anne M. Fourie and Alice Lee-Dutra, 58, 
Chapter 4 CRTH2 Antagonists L. Nathan Tumey, 104, 
Section 2: Kinases, 
Chapter 5 Dual Inhibition of Phosphodiesterase-4 and p38 MAP Kinase: A Strategy for Treatment of Chronic Inflammatory Diseases Wolfgang Albrecht and Stefan Laufer, 137, 
Chapter 6 MAPKAP Kinase 2 (MK2) as a Target for Anti-inflammatory Drug Discovery Jeremy J. Edmunds and Robert V. Talanian, 158, 
Chapter 7 Syk Kinase Inhibitors Neelu Kaila, Mark S. Ryan, Atli Thorarensen and Eddine Saiah, 181, 
Chapter 8 Janus Kinases – Just Another Kinase or a Paradigm Shift for the Treatment of Autoimmune Disease? Michael Skynner, Phil Jeffrey, Michael Binks and Michael Woodrow, 211, 
Chapter 9 IKKb as a Therapeutic Intervention Point for Diseases Related to Inflammation Erick R. R. Young, 255, 
Chapter 10 Bruton's Tyrosine Kinase (Btk) Mark E. Schnute, Adrian Huang and Eddine Saiah, 297, 
Section 3: GPCRs, 
Chapter 11 CCR1 J. Robert Merritt and Annette Gilchrist, 329, 
Chapter 12 CCR2 Antagonists for the Treatment of Diseases Associated with Inflammation Cuifen Hou and Zhihua Sui, 350, 
Chapter 13 Recent Advances in Selective CB2 Agonists for the Treatment of Pain E. J. Gilbert and C. A. Lunn, 391, 
Section 4: Sphingolipids, 
Chapter 14 S1P Receptor Agonists Craig A. Miller, 417, 
Chapter 15 Tipping the Balance of Sphingosine 1-Phosphate Production: Sphingosine Kinases and Sphingosine 1-Phosphate Lyase as Immune Therapeutic Targets Tamas Oravecz and David Augeri, 444, 
Section 5: Steroid Hormone Receptors, 
Chapter 16 Non-steroidal Dissociated Glucocorticoid Receptor Agonists Hossein Razavi and Christian Harcken, 481, 
Subject Index, 517, 

CHAPTER 1

Microsomal Prostaglandin E2 Synthase-1

ANDREAS KOEBERLE AND OLIVER WERZ

Prostaglandins (PGs) are pivotal bioactive lipid mediators that mediate inflammatory reactions but also contribute to various homeostatic biological processes. The cyclooxygenase (COX) isoenzymes namely COX-1 (constitutively expressed in numerous cell types and thought to provide PGs mainly for physiological functions) and COX-2 (an inducible isoform in inflammatory cells, primarily producing PGs relevant for inflammation, fever and pain) initiate PG biosynthesis from arachidonic acid. The non-steroidal anti-inflammatory drugs (NSAIDs) or COX-2 selective drugs (coxibs) inhibit COX activities and thus exert potent anti-inflammatory and analgesic effects but may also cause severe side-effects such as gastrointestinal and renal complications. The latter effects have been ascribed to the general suppression of constitutively formed prostanoids such as COX-1-derived cytoprotective PGE2 and prostacyclin (PGI2) in gastroduodenal epithelium. Even though coxibs have an improved gastrointestinal tolerance, recent clinical studies revealed small but significantly increased risks for cardiovascular events such as myocardial infarction, stroke, systemic and pulmonary hypertension, congestive heart failure and sudden cardiac death. Apparently, the imbalance between the anti-thrombotic and vasodilatory PGI2 on one hand and the pro-thrombotic TxA2 on the other are responsible for those side-effects. Since side-effects are particularly problematic in the therapy of chronic pathologies, such as rheumatoid arthritis, requiring long-term drug application, there is a strong need for novel potent and safe anti-inflammatory drugs lacking such toxicity.

1.1 Function of PGE2 as Bioactive Mediator

Among the PGs, PGE2 is the most prominent mediator in inflammation, fever and pain but also has physiological functions in the gastrointestinal tract, the kidney and in the immune and the central nervous system. PGE2 mediates its bioactivities essentially by four G-protein coupled PGE2 receptor subtypes (EP1–EP4) in diverse tissues, supported by experiments with knockout mice deficient (-/-) in EP receptor subtypes and selective EP receptor antagonists. For example, deletion of respective EP receptor subtypes significantly reduced exudate formation in carrageenan-induced mouse pleurisy (EP2 and EP3), diminished arachidonic acid-induced cutaneous inflammation (EP3) and inflammation and joint destruction in collagen (EP4), as well as collagen-antibody-induced arthritis (EP4 and EP2). In lipopolysaccharide-challenged mice, activation of the hypothalamo-pituitary-adrenal axis and systemic illness including the febrile response in response to PGE2 was mainly ascribed to the EP3 receptor (although other subtypes are also involved). Regarding pain sensation, all four EP receptors seemingly contribute, but the EP-receptor subtype involved depends on the nociceptive stimulus and/or the pre-treatment of the animals. For example, the EP1 receptor mediates the acute pain response in the acetic acid-induced writhing test in mice, whereas EP3 is the critical receptor for LPS-induced hyperalgesia. However, PGE2 also exerts immunosuppressive effects contributing to the resolution of inflammation, mediates protection of gastrointestinal mucosa and regulation of natriuresis and regulates renal blood flow and blood pressure.

1.2 PGE2 Biosynthesis by mPGES-1

PGE2 synthases (PGES) perform the terminal step in the biosynthesis of PGE2, that is, the isomerization of the COX-derived peroxide PGH2 to PGE2. Three terminal isoforms of PGE2 synthases have been cloned and characterized. Co-transfection of COX-1 and -2 with PGES isoenzymes in mammalian cells suggests that molecular interactions may cause preferential functional coupling. While the constitutively expressed cytosolic PGE2 synthase (cPGES) was found to be coupled to COX-1, mPGES-1 is predominantly involved in COX-2-mediated PGE2 production. mPGES-2 is also constitutively expressed, uses PGH2 supplied by COX-1 and COX-2 and contributes to basal PGE2 synthesis but its functional role in physiology and patho-physiology is still elusive.

1.3 Structure and Biochemical Properties of mPGES-1

Human mPGES-1 (16 kDa) is a member of the membrane-associated proteins involved in eicosanoid and glutathione metabolism (MAPEG) family and is characterized by a high turnover number for PGH2 (kcat = 50 s-1). The enzyme is membrane-bound and localized to the microsomal fraction after subcellular fractionation. Km values of 14–160 µM and 710–750 µM were reported for PGH2 and glutathione, respectively.

The homotrimeric structure of mPGES-1 was recently determined at low resolution by electron crystallography. The monomers consist of four transmembrane helices (TM1-4) and enclose an inner core with a funnel-shaped opening towards the cytoplasm. The essential cofactor glutathione is bound in a U-shaped conformation at the interface between the subunits. Glutathione was proposed to attack the peroxide of PGH2 in the active site via its thiol-group during the catalytic cycle. Mutation studies suggest Arg126, which is located near the thiol of glutathione, as catalytic residue and Thr-131,...

Details zur Ausgabe

• Verlag: Royal Society of Chemistry
• Erscheinungsdatum: 2012
• Sprache: Englisch
• ISBN 10: 1849734135
• ISBN 13: 9781849734134
• Einband: Gebundene Ausgabe
• Anzahl der Seiten: 528
• Herausgeber: Levin Jeremy I, Laufer Stefan
• Kontakt zum Hersteller: Nicht verfügbar
• Verantwortliche Person: gpsr@libri.de; gpsr@libri.de; ; Friedensallee 273; Hamburg; 22763; Deutschland