Improved Non-Steroid Anti-Inflammatory Drugs: COX-2 Enzyme Inhibitors

248 Pages·2011·26.18 MB·English

by  Sir John R. Vane

Improved Non-Steroid
Anti-Inflammatory Drugs
COX-2 Enzyme Inhibitors
The conference organisers wish to thank
Boehringer
Ingelheim
for an educational grant to support this conference
Chapter 2 Figure' A Molescript diagram of the COX-' dimer derived from the 3.' Ar efined structure.
Heme groups are shown in red, Tyr385 in green and flurbiprofen in yef/ow. The bound detergent
molecules are shown in orange where the two near the asterisk are involved in crystBl contacts; the
other detergent molecule which is in the cyclooxygenase channel also appears in the other monomer.
Helices A, B, C, 0 of the membrane binding domain as welf as the site of trypsin cleavage, Arg277, are
also labeffed
Chapter 5 Figure 10 NSAIO binding approach to membrane. Molecular depiction of the binding of an
NSAIO to the lipid bilayer structure as a necessary and first step to binding to the COX enzyme.
Improved Non-Steroid
Anti-Inflammatory Drugs
COX-2 Enzyme Inhibitors
Edited by
SIR JOHN VANE, DR JACK BOTTING and DR REGINA BOTTING
The William Harvey Research Institute, Saint Bartholomew's Hospital
Medical College, London, United Kingdom
Proceedings of a conference held
on October 10-11, 1995,
at Regent's College, London
KLUWER ACADEMIC PUBLISHERS WILLIAM HARVEY
DORDRECHTIBOSTONILONDON PRESS
Distributors
for the United States and Canada: Kluwer Academic Publishers, PO Box 358, Accord Station,
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for all other countries: Kluwer Academic Publishers Group, Distribution Center, PO Box 322,
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A catalogue record for this book is available from the British Library
ISBN-13 :978-94-01 0-9031-5 e-ISBN-13 :978-94-01 0-9029-2
DOl: 10.1007/978-94-010-9029-2
Copyright
© 1996 by Kluwer Academic Publishers and William Harvey Press
Softcover reprint of the hardcover 1s t edition 1996
All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or
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Published in the United Kingdom by Kluwer Academic Publishers, PO Box 55, Lancaster, UK, and
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Kluwer Academic Publishers BY incorporates the publishing programmes of D. Reidel,
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Typeset by Lasertext Ltd, Stretford, Manchester.
Contents
List of contributors vii
Preface IX
1 Overview - mechanisms of action of anti-inflammatory drugs
John Vane and Regina Botting
2 The three-dimensional structure of cyc100xygenases
R. Michael Garavito 29
3 The dilemma of two cyc1ooxygenases: identifying the roles of
COX-1 and COX-2 in inflammation and apoptosis
Daniel Simmons, Xiaojun Lu, William Bradshaw and Weilin Xie 45
4 Inducible enzymes with special reference to COX-2 in the
inflammatory response
Derek Willoughby, Annette Tomlinson, Derek Gilroy and
Dean Willis 67
5 NSAID mechanism of action: the role of intracellular
pharmacokinetics
Leo Berbette, Michelle Vecchiarelli and Gunther Trummlitz 85
6 Differential inhibition of COX-1 and COX-2 in vitro and
pharmacological profile in vivo of NSAIDs
Michel Pairet and Gunther Engelhardt 103
7 COX-2 expression and inhibition in human monocytes
Carlo Patrono, Paola Patrignani, Maria Panara,
Francesco Cipollone, Giovanna Santini, Maria Sciulli,
Maria Rotondo, Roberto Padovano and
Maria di Giamberardino 121
8 Expression and regulation of COX-2 in synovial tissues of
arthritic patients
Leslie Crofford 133
V
vi COX-2 ENZYME INHIBITORS
9 An inhibitor of injury-induced COX-2 transcriptional activation
elicits neuroprotection in a brain damage model
Nicolas Bazan, Geoffrey Allan and Victor Marcheselli 145
10 COX-2 expression in labour
Phillip Bennett and Donna Slater 167
11 Re-evaluation of gut toxicity of NSAIDs
D. Nicholas Bateman 189
12 NSAID: can renal side effects be avoided?
Jiirgen Frolich and Dirk Stichtenoth 203
13 Pharmacology, safety data and therapeutics of COX-2 inhibitors
Paul Emery 229
Index 243
List of Contributors
D. Nicholas Bateman
Regional Drugs and Therapeutics Centre, Wolfson Unit, Claremont Place,
Newcastle-upon-Tyne NEI 4LP, UK,
Nicolas G. Bazan
Department of Ophthalmology and LSU Neuroscience Center of Excellence, Louisiana
State University Medical Center, School of Medicine, 2020 Gravier Street, Suite B, New
Orleans LA 70112, USA
Co-authors: Geoffrey Allan and Victor Marcheselli
Phillip Bennett
Royal Postgraduate Medical School, Institute of Obstetrics and Gynaecology, Queen
Charlotte's and Chelsea Hospital, Goldhawk Road, London W6 OXG, UK
Co-author: Donna Slater
Leslie J. Crofford
Department of Internal Medicine, Division of Rheumatology, University of Michigan,
Ann Arbor, MI 48109, USA
Paul Emery
Rheumatology and Rehabilitation Research Unit, University of Leeds, 36 Clarendon
Road, Leeds LS2 9JT UK
Jiirgen C. Frolich
Institute of Clinical Pharmacology, Hannover Medical School, 30623 Hannover,
Germany
Co-author: Dirk Stichtenoth
R. Michael Garavito
Department of Biochemistry, 522 Biochemistry Building, Michigan State University,
East Lansing, MI 48824-1319, USA
Leo G. Herbette
Biomolecular Structure Analysis Center, University of Connecticut Health Center,
Farmington, CT 06030, USA
Co-authors: Michelle Vecchiarelli and Gunther Trummlitz
Michel Pairet
Department of Biological Research, Boehringer Ingelheim Research Laboratories,
Birkendorfer Strasse 65, 88397 Biberach an der Riss, Germany
Co-author: Gunther Engelhardt
vii
viii COX-2 ENZYME INHIBITORS
Carlo Patrono
University of Chieti, 'G D'Annunzio' School of Medicine, Via dei Vestini 31, 66013
Chieti, Italy
Co-authors: Paola Patrignani, Maria Panara, Francesco Cipollone, Giovanna Santini,
Maria Sciulli, Maria Rotondo, Roberto Padovano and Maria di Giamberardino
Daniel L. Simmons
Department of Chemistry and Biochemistry, E280 BNSN, Brigham Young University,
Provo, UT 84602, USA
Co-authors: Xiaojun Lu, William Bradshaw and Weilin Xie
John R. Vane
The William Harvey Research Institute, St Bartholomew's Hospital Medical College,
Charterhouse Square, London ECIM 6BQ, UK
Co-author: Regina M. Botting
Derek Willoughby
Department of Experimental Pathology, St Bartholomew's Hospital Medical College,
William Harvey Research Institute, London EClM 6BQ, UK
Co-authors: Annette Tomlinson, Derek Gilroy and Dean Willis
Preface
In 1971, Vane proposed that the mechanism of action of the aspirin-like drugs
was through their inhibition of prostaglandin biosynthesis. Since then, there has
been intense interest in the interaction between this diverse group of inhibitors
and the enzyme known as cyclooxygenase (COX). It exists in two isoforms,
COX-l and COX-2 (discovered some 5 years ago). Over the last two decades
several new drugs have reached the market based on COX-l enzyme screens.
Elucidation of the three-dimensional structure of COX-l has provided a new
understanding for the actions of COX inhibitors. The constitutive isoform of
COX, COX-l has clear physiological functions. Its activation leads, for instance,
to the production of prostacyclin which when released by the endothelium is
anti-thrombogenic and anti-atherosclerotic, and in the gastric mucosa is cyto
protective. COX-l also generates prostaglandins in the kidney, where they help
to maintain blood flow and promote natriuresis. The inducible isoform, COX-2,
was discovered through its activity being increased in a number of cells by pro
inflammatory stimuli. A year or so later, COX-2 was identified as a distinct
isoform encoded by a different gene from COX-I. COX-2 is induced by
inflammatory stimuli and by cytokines in migratory and other cells. Thus the
anti-inflammatory actions of non-steroid anti-inflammatory drugs (NSAIDs)
may be due to the inhibition of COX-2, whereas the unwanted side-effects such
as irritation of the stomach lining and toxic effects on the kidney are due to
inhibition of the constitutive enzyme, COX-I. This hypothesis has led to intense
research to establish, inter alia, the relative activities of the currently used
NSAIDs against COX-l and COX-2, the sites of expression of COX-2 and the
therapeutic activity and toxicity profile of new, highly selective COX-2
inhibitors.
The following chapters, written by leaders in the field, review the current
status of this research. In the next few years, we can expect improved therapy of
inflammatory disease, arising from further knowledge of the pathophysiological
significance of the COX enzymes.
John R. Vane
ix
1 Overview - mechanisms of action
of anti-inflammatory drugs
J.R. VANE and R.M. BOTTING
Inflammation is the response of living tissues to injury. It involves a complex
battery of enzyme activation, mediator release, extravasation of fluid, cell
migration, tissue breakdown and repair. This overview will concentrate on the
actions of anti-inflammatory drugs, with special reference to the prostaglandin
system. This system is activated by phospholipase A2, which liberates arachi
donic acid, the substrate for cyclooxygenase (COX or PGH2 synthase). This
leads to an increased production of prostaglandins (Figure 1). Prostaglandin E2
is the predominant eicosanoid detected in inflammatory conditions in man
ranging from experimental acute oedema and sunburn through to chronic
arthritis. Because inflammation is one of the few conditions in which PGE2 is a
major product of COX it is possible that the process of inflammation directs the
enzymic pathway towards this product. A second enzyme, 5-lipoxygenase
converts arachidonic acid to the leukotrienes1, which are important mediators of
asthma, but this aspect will not be discussed here.
Prostaglandin E2 accounts for the characteristic vasodilatation and erythema
(redness) seen in acute inflammation2. Vasodilatation increases the flow of blood
through inflamed tissues and this augments the extravasation of fluid (oedema)
caused by agents which increase vascular permeability such as bradykinin and
histamine3• Prostaglandin E2 also acts synergistically with other mediators to
produce inflammatory pain: although it has no direct pain-producing activity,
PGE2 sensitizes receptors on afferent nerve endings to the actions of bradykinin
and histamine4• PGE2 is also a potent pyretic agent and its production, stimulated
by the release of interleukin-l (IL-l), in bacterial and viral infections contributes
to the associated feverS.
Many other COX products have been detected in inflammatory lesions. These
include PGF2a, PGD2, prostacyclin (as 6-keto-PGF1u) and thromboxane ~ (TXAz;
as TXB2), but these are usually present at less than a quarter of the con
centrations of PGE2. Prostacyclin is probably the most important of these
products in terms of inflammatory signs, for it is also a potent vasodilator and is
a more potent hyperalgesic agent than PGEz- It is likely, therefore, that both
PGE and prostacyclin contribute to the development of inflammatory erythema
2
and pain6.
There was a new dawn in inflammatory research when Needleman and his
colleagues found that COX activity was substantially increased by bacterial
endotoxin in human monocytes in vitr07 and in mouse peritoneal macrophages