Selective COX-2 Inhibitors: Pharmacology, Clinical Effects and Therapeutic Potential

152 Pages·1998·5.237 MB·English

by  J. R. Vane, R. M. Botting (auth.), Sir John Vane, Dr Jack Botting (eds.)

Selective COX-2 Inhibitors
Pharmacology, Clinical Effects
and Therapeutic Potential
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
Selective COX-2 Inhibitors
Pharmacology, Clinical Effects
and Therapeutic Potential
Edited by
SIR JOHN VANE and DR JACK BOTTING
The William Harvey Research Institute, Saint Bartholomew's
and the Royal London School of Medicine and Dentistry,
Charterhouse Square, London, United Kingdom
Proceedings of a conference held
on March 20-21, 1997
in Cannes, France
The conference organisers wish to thank
Boehringer
Ingelheim
for an educational grant to support this conference
t4
SPRINGER SCIENCE+BUSINESS MEDIA, B.V. WILLIAM ^ HARVEY
PRESS
A catalogue record for this book is available from the Library of Congress.
ISBN 978-94-010-6041-7 ISBN 978-94-011-4872-6 (eBook)
DOI 10.1007/978-94-011-4872-6
Copyright
© 1998 by Springer Science+Business Media Dordrecht
Originally published by Kluwer Academic Publishers in 1998
All 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.V..
Contents
List of Contributors vii
Preface ix
1 Mechanism of action of anti-inflammatory drugs:
an overview
JR Vane, RM Botting
2 The structure of human COX-2 and selective inhibitors 19
MF Browner
3 Differential inhibition of COX-I and COX-2 by NSAIDs: 27
a summary of results obtained using various test systems
M Pairet, J van Ryn, A Mauz, H Schierok, W Diederen,
D Turck, G Engelhardt
4 COX-2 in brain and retina: role in neuronal survival 47
NG Bazan, VL Marchesel/i, PK Mukherjee, WJ Lukiw,
WC Gordon, D Zhang
5 COX-2 and apoptosis: NSAIDs as effectors of programmed
cell death 55
DL Simmons, ML Madsen, PM Robertson
6 Inhibition of intestinal tumorigenesis via selective
inhibition of COX-2 67
RN DuBois, H Sheng, J Shao, C Williams, RD Beauchamp
7 CycIooxygenase enzymes in human vascular disease 73
C Patrono, F Cipollone, GRenda, P Patrignani
8 Gastrointestinal effects of NSAIDs 79
CJ Hawkey
9 Renal side effects of NSAIDs: role of COX-I and COX-2 87
JC Fro/ich, DO Stichtenoth
10 Aspirin-induced asthma and cycIooxygenases 99
RJ Gryglewski
v
vi SELECTIVE COX-2 INHIBITORS
11 New classification of aspirin-like drugs lO9
H Fenner
12 New highly selective COX-2 inhibitors 117
AW Ford-Hutchinson
13 Specific COX-2 inhibitors: from bench to bedside 127
P Isakson, B Zweifel, J Masferrer, C Koboldt, K Seibert,
R Hubbard, S Geis, P Needleman
14 Meloxicam: selective COX-2 inhibition in clinical practice 135
DE Furst
Index 145
List of Contributors
Nicolas G. Bazan
Neuroscience Center of Excellence, Louisiana State University, Medical Center,
School of Medicine, 2020 Gravier Street, New Orleans, LA 70112, USA.
Co-authors: Victor Marcheselli, Pranab Mukherjee,·Walter Lukiw, William Gordon
and Daoling Zhang
Michelle F. Browner
Molecular Structure Department, Roche Bioscience, 3401 Hillview Avenue, Palo
Alto, CA 94303, USA.
Raymond N. DuBois
Department of Medicine, Vanderbilt University Medical Center, Nashville, TN
37232-2279, USA.
Co-authors: Hongmiao Sheng, Jinyi Shao, Christopher Williams and Daniel
Beauchamp
Helmut Fenner
Swiss Federal Institute of Technology, Zurich, Switzerland.
Anthony Ford-Hutchinson
Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway,
Kirkland, Quebec H9H 3Ll, Canada.
Jiirgen C. Frolich
Institute of Clinical Pharmacology, Hannover Medical School, 30623 Hannover,
Germany.
Co-author: Dirk o. Stichtenoth
Daniel E. Furst
Arthritis Clinical Research Unit, Virginia Mason Research Center, 1000 Seneca
Street, Seattle, WA 98101, USA.
Ryszard J. Gryglewski
Department of Pharmacology, Jagiellonian University Medical College,
Grzegorzecka 16, 31-531 Cracow, Poland.
Christopher J. Hawkey
Division of Gastroenterology, University Hospital, Nottingham NG7 2UH, UK.
vii
viii SELECTIVE COX-2 INHIBITORS
Philip Needleman
G. D. Searle Research and Development, 700 Chesterfield Village Parkway, St Louis,
MO 63198, USA.
Co-authors: Peter Isakson, Ben Zweifel, Jaime Masferrer, Carol Koboldt, Karen
Seibert, Richard Hubbard and Steven Geis
Michel Pairet
Department of Biological Research, Boehringer Ingelheim Research &
Development, Birkendorfer Str. 65, 88397 Biberach aid Riss, Germany.
Co-authors: Joanne van Ryn, Annerose Mauz, Hans Schierok, Willi Diederen,
Dietrich Turck and Gunther Engelhardt
Carlo Patrono
Center for Experimental Therapeutics, University of Pennsylvania, 905 Stellar
Chance Laboratories, 422 Curie Boulevard, Philadelphia, PA 19104-61100, USA.
Co-authors: Francesco Cipollone, Giulia Renda and Paola Patrignani
Daniel L. Simmons
Department of Chemistry and Biochemistry, E280 BNSN, Brigham Young
University, Provo, UT 84602, USA.
Co-authors: Matthew Madsen and Philip Robertson
John R. Vane
The William Harvey Research Institute, St Bartholomew's and the Royal London
School of Medicine and Dentistry, Queen Mary and Westfield College,
Charterhouse Square, London ECI M 6BQ, UK.
Co-author: Regina Botting
Preface
The mainstay of therapy for rheumatoid disease is the non-steroid antiinflammatory
drugs (NSAIDs), despite their inherent gastrointestinal toxicity and ability to cause
renal damage in susceptible patients. The theory that the beneficial and toxic effects
of NSAIDs stem from a reduction in prostanoid production through inhibition of
cyclooxygenase implied that particular toxicities were inevitable with NSAIDs and
would always be correlated with efficacy. However, over the years, it became apparent
that at therapeutic doses, some NSAIDs had greater toxic side-effects than others, a
fact not explained by the general theory. A significant clarification arose from the
discovery that there are two distinct isoforms of COX, a constitutive enzyme (COX-I)
responsible for the production of prostanoids necessary for platelet aggregation and
protection of the gastric mucosa and kidney; and an inducible enzyme (COX-2) that
is newly synthesized at sites of tissue damage and produces prostaglandins that
manifest pathological effects. It became clear that different NSAIDs had greater or
lesser effects on COX-I when used in therapeutic doses, explaining the variation in
side-effects. '
The elucidation of the crystal structure of these different enzymes and the skills of
medicinal chemists have led to the synthesis of new chemicals with a selectivity for the
inducible enzyme, and thus with therapeutic efficacy without those toxic effects result
ing from inhibition of the constitutive enzyme. A few compounds, such as meloxicam,
etodolac and nimesulide, discovered by empirical screening in rats, also turned out to
have selectivity towards COX-2. Interestingly, the focus on COX enzymes has exposed
other putative sites for the actions of their prostanoid products, with the consequent
possibility of new uses for NSAIDs such as in the prophylaxis or treatment of cancer,
preventing pre-term delivery and possibly in treating Alzheimer's disease. The
therapeutic value of new selective COX-2 inhibitors, and the pathophysiological
significance of COX-I and COX-2, are reviewed in the following chapters presented
by recognized authorities in the field.
John R. Vane
Jack H. Botting
ix
1 Mechanism of action of anti
inflammatory drugs: an overview
J. R. VANE and R. M. BOTTING
Among the many mediators of inflammation, the prostaglandins (PGs) are of great
importance. They are released by almost any type of chemical or mechanical stimulus.
The key enzyme in their synthesis is prostaglandin endoperoxide synthase (PGHS) or
cyclooxygenase (COX) which possesses two catalytic sites. The first, a cyclooxygenase
active site, converts arachidonic acid to the endoperoxide PGG2• The second, a
peroxidase active site, then converts the PGG2 to another endoperoxide PGH2• PGH2
is further processed by specific isomerases to form PGs, prostacyclin and
thromboxane A2• Of the PGs, PGE2 and prostacyclin are the main inflammatory
mediators. Cyclooxygenase activity has long been studied in preparations from sheep
seminal vesicles and a purified, enzymatically-active COX was isolated in 19761• We
now know that COX exists in at least' two isoforms, COX-I and COX-2.
Over 25 years ago, Vane proposed that the mechanism of action of the aspirin-like
drugs (non-steroid anti-inflammatory drugs; NSAIDs) was through the inhibition of
PG biosynthesis2 and there is now a general acceptance of the theory. The inhibition
by aspirin is due to the irreversible acetylation of the COX site of PGHS, leaving the
peroxidase activity of the enzyme unaffected. In contrast to this unique irreversible
action of aspirin, other NSAIDs such as ibuprofen or indomethacin produce revers
ible or irreversible COX inhibition by competing with the substrate, arachidonic acid,
for the active site of the enzyme.
The inhibition of PG synthesis by NSAIDs has been demonstrated in a wide variety
of systems, ranging from microsomal enzyme preparations, cells and tissues to whole
animals and man. For instance, the concentration of PGE is about 20 ng/ml in the
2
synovial fluid of patients with rheumatoid arthritis3• This decreases to zero in patients
taking aspirin, a good clinical demonstration of the effect of this drug on PG synthesis.
Over the last two decades, several new drugs have reached the market based on COX-I
enzyme screens.
Garavito and his colleagues4 have determined the three dimensional structure of
COX-I, providing a new understanding for the actions of COX inhibitors. Each dimer
of COX-I comprises three independent folding units: an epidermal growth factor-like
domain, a membrane binding motif and an enzymatic domain. The sites for peroxidase
and COX activity are adjacent but spatially distinct. The conformation of the
membrane-binding motif strongly suggests that the enzyme integrates into only a
single leaflet of the lipid bilayer and is thus a monotopic membrane protein. Three of
the helices of the structure form the entrance to the COX channel and their insertion
into the membrane could allow arachidonic acid to gain access to the active site from
the interior of the bilayer. The COX active site is a long, hydrophobic channel and
1