New Targets in Inflammation Inhibitors of COX-2 or Adhesion Molecules The publishers are grateful to Dr Michelle Browner, Roche Bioscience, Palo Alto, California, for the schematic diagram of the human COX-2 dimer shown on the cover New Targets in In8ammation Inhibitors of COX-2 or Adhesion Molecules Edited by DR NICOLAS BAZAN*, DR JACK BOTTING and SIR JOHN VANE The William Harvey Research Institute, Saint Bartholomew's Hospital Medical College, London, United Kingdom *Neuroscience Center, Louisiana State University, New Orleans, USA Proceedings of a conference held on April 15 -16, 1996, in New Orleans, USA, supported by an educational grant from Boehringer "" 11111111 Ingelheim 80EHRINGfR INGE~HEIM SPRINGER-SCIENCE+BUSINESS MEDIA, B.V. WILLIAM HARVEY PRESS A catalogue record for this book is available from the British Library ISBN 978-94-010-6265-7 ISBN 978-94-011-5386-7 (eBook) DOI 10.1007/978-94-011-5386-7 Copyright © 1996 by Springer Science+Business Media Dordrecht Originally published by Kluwer Academic Publishers in 1996 Softcover reprint ofthe hardcover 1s t edition Ali rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without prior permission from the publishers, Springer-Science+Business Media, B.Y. Typeset by Lasertext Ltd, Stretford, Manchester. Contents List of contributors Vll Preface ix 1 The history of anti-inflammatory drugs and their mechanism of action l. R. Vane and R. M. Botting 2 Structure of prostaglandin H2 synthase-l (COX-I) and its NSAID binding sites p. l. Loll 13 3 Differential inhibition of cyclooxygenases 1 and 2 by NSAIDs M. Pairet, L. Churchill and G. Engelhardt 23 4 Blockade of inflammatory hyperalgesia and cyclooxygenase-2 S. H. Ferreira 39 5 Brain COX-2 in experimental models of epilepsy and stroke: signalling pathways leading to enhanced expression N. G. Bazan, V. M. Marcheselli, G. Allan, K. Van Meter and l. P. Moises 47 6 New highly selective cyclooxygenase-2 inhibitors A. W. Ford-Hutchinson 55 7 Characteristics of cyclooxygenase-l and cyclooxygenase-2-deficient mice S. G. Morham and R. Langenbach 63 8 X-ray crystal structure of human cyclooxygenase-2 M. Browner 71 9 Risk of gastrointestinal side effects caused by non-steroid anti-inflammatory drugs (NSAIDs) H. lick 75 10 Expression and regulation of cyclooxygenase-2 in synovial tissues of arthritic patients L. l. Crofford 83 v vi NEW TARGETS IN INFLAMMATION 11 Differential target tissue presentation and COX-I/COX-2 inhibition by non-steroid anti-inflammatory drugs: a rationale for a new classification H. Fenner 93 12 Clinical experience with meloxicam, a selective COX-2 inhibitor W Bolten 105 13 Enzymatic regulation of the prostaglandin response in a human model of inflammation B. F. Adam and G. A. Fitzgerald 117 14 Cyclooxygenase-2 and intestinal cancer R. N. DuBois, A. Radhika, 1. Shao, M. Tsujii, H. Sheng, O. Kobyashi, R. D. Beauchamp and C. S. Williams 123 15 Cytokines and adhesion molecules in the lung inflammatory response P. A. Ward 131 16 Adhesion molecules as targets for therapy in rheumatoid arthritis P. E. Lipsky, A. F. Kavanaugh, H. Schulze-Koops and L. S. Davis 139 Index 145 List of Contributors N. G. Bazan LSU Neuroscience Center, Louisiana State University Medical Center, School of Medicine, New Orleans, LA 70112, USA Co-authors: V. M. Marcheselli, G. Allan, K. van Meter and J. P. Moises W. Bolten Rheumaklinik Wiesbaden II, Leibnizstrasse 23, 65191 Wiesbaden, Germany M. Browner Molecular Structure Department, Roche Bioscience, 3401 Hillview Avenue, Palo Alto, CA 94303, USA L. J. Crofford Department of Internal Medicine, University of Michigan, 200 Zina Pitcher Place, Ann Arbor, MI 48109-0531, USA R. N.DuBois Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232-2279, USA Co-authors: A. Radhika, J. Shao, M. Tsujii, H. Sheng, O. Kobyashi, R. D. Beauchamp and C. S. Williams H. Fenner Swiss Federal Institute of Technology, Zurich, Switzerland S. H. Ferreira Departamento de Farmacologia, Faculdade de Medicina de Ribeirao Pre to, USP, CEP 14.049-900, Ribeirao Preto, Sao Paulo, Brazil A. W. Ford-Hutchinson Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Quebec H9H 3L1, Canada G. A. Fitzgerald The Center for Experimental Therapeutics, The University of Pennsylvania, 905 Stellar Chance Laboratories, 422 Curie Boulevard, Philadelphia, PA 19104, USA Co-author: B. F. McAdam vii viii NEW TARGETS IN INFLAMMATION H. Jick Boston Collaborative Drug Surveillance Program, Boston University Medical Center, 11 Muzzey Street, Lexington, MA 02173, USA P. E. Lipsky Harold C. Simmons Arthritis Research Center, University of Texas Southwestern Medical School, 5323 Harry Hines Boulevard, Dallas, TX 75235-8884, USA Co-authors: A. F. Kavanaugh, H. Schulze-Koops and L. S. Davis P. J. Loll Department of Pharmacology, University of Pennsylvania School of Medicine, 3620 Hamilton Walk, Philadelphia, PA 19104-6084, USA S.Morham Department of Pathology, University of North Carolina at Chapel Hill, NC 27599-7525, USA Co-author: R. Langenbach M. Pairet Department of Biological Research, Boehringer Ingelheim Research Laboratories, Birkendorfer Strasse 65, 88397 Biberach an der Riss, Germany Co-authors: L. Churchill and G. Engelhardt J.R. Vane The William Harvey Research Institute, St Bartholomew's Hospital Medical College, Charterhouse Square, London ECIM 6BQ, UK Co-author: R. M. Botting P.A. Ward Department of Pathology, University of Michigan Medical School, 1301 Catherine Road, Ann Arbor, MI 48109-0602, USA Preface For the past 100 years the mainstay of therapy for rheumatoid arthritis (RA) has been aspirin or other drugs of the non-steroid anti-inflammatory group. In 1971 Vane pro posed that both the beneficial and toxic actions of these drugs was through inhibition of prostaglandin synthesis. The recent discovery that prostaglandins responsible for pain and other symptoms at inflammatory foci are synthesized by an inducible cyclooxygenase (COX-2) that is encoded by a gene distinct from that of the consti tutive enzyme (COX-I) provided a new target for therapy of RA. A drug that would selectively inhibit COX-2 would hopefully produce the symptomatic benefit provided by existing NSAIDs without the gastrointestinal and renal toxicity due to the inhibition of COX-I. Drugs selective for COX-2 are now available. Experimental studies have shown them to be effective with minimal toxicity, and in clinical trials gastric and renal toxicities are less. Highly selective COX-2 inhibitors, perhaps designed with knowledge of the crystal structures of COX-I and COX-2, are also available. Other experimental studies, including those in animals lacking effective genes for COX-lor COX-2 and in experimental carcinomas, suggest there is still much to be learned of the pathophysiological functions of these enzymes. The inflammatory response is a complex reaction involving many mediators that derive from white blood cells, endothelial cells and other tissues. Preliminary data have revealed that inhibitors of the cytokines and adhesion molecules that play a crucial role in the migration of white cells to inflammatory sites may be useful in RA. These various issues are reviewed by experts who have contributed the following chapters. Clearly such work will provide the basis for greatly improved treatments or even cures for inflammatory disease. Nicolas G. Bazan Jack H. Botting JohnR. Vane ix 1 The history of anti-inflammatory drugs and their mechanism of action J. R. VANE and R. M. BOTTING The history of the anti-inflammatory drugs begins with the early use of decoctions or preparations of plants containing salicylate. Salicylic acid and salicylates are constituents of several plants long used as medicaments. About 3500 years ago the Egyptian Ebers papyrus recommended the application of a decoction of the dried leaves of myrtle to the abdomen and back to expel rheumatic pains from the womb. A thousand years later Hippocrates recommended the juices of the poplar tree for treating eye diseases and those of willow bark to relieve the pain of childbirth and to reduce fever. All of these medicinal remedies contain salicylates. In AD 30 Celsus described the four classic signs of inflammation (rubor, calor, dolor and tumor; or redness, heat, pain and swelling) and used extracts of willow leaves to relieve them. Throughout the Roman times of Pliny the Elder, Dioscorides and Galen the use of salicylate-containing plants was further developed and willow bark was recommended for mild to moderate pain. In China and other parts of Asia also, salicylate-containing plants were being applied therapeutically. The curative effects of Salix and Spir(£a species were also known to the early inhabitants of North America and South Africa. Through the Middle Ages further uses for salicylates were found, such as plasters to treat wounds and various other external and internal applications, including the treatment of menstrual pain and discomfort of dysentery. However, willows were needed for basket making so the women herbalists of those days turned to other related plants: they grew meadowsweet (Spir(£a ulmaria) in their herb gardens and made decoctions from the flowers. The first 'clinical trial' of willow bark to be published in England was made by a country parson, the Reverend Edward Stone of Chipping Norton in Oxfordshirel. On June 2, 1763, Edward Stone presented a report to the Royal Society on the use of willow bark in fever. He had accidentally tasted it and was surprised by its extraordinary bitterness, which reminded him of the taste of cinchona bark (containing quinine), then being used to treat malaria. He believed in the 'doctrine of signatures' which dictated that the cures for diseases would be found in the same locations where the malady occurs. Since the "willow delights in a moist and wet soil, where agues chiefly abound", he gathered a pound of willow bark, dried it over a baker's oven for three months then ground it to a powder. His greatest success was with doses of I dram (1.8g), which he reported using in about 50 patients with safety and success. He concluded his paper by saying "I have no other motives for publishing this valuable