The Search for Anti-Inflammatory Drugs: Case Histories from Concept to Clinic

309 Pages·1995·7.1 MB·English

by  Ivan G. Otterness (auth.)

The Search for
Anti-Inflammatory Drugs
Case Histories
from Concept to Clinic
The cover figure depicts metabolism of endogenous and exogenous
substrates by S-lipoxygenase (S-LO) in human neutrophils. In the
bottom half of the figure, a stimulus provokes the release of endogenous
arachidonic acid (AA) from membrane phospholipids (PL) and activates
the S-LO/S-LO activator protein (FLAP) system which then converts free
AA to leukotriene B4 (LTB4). In the top half of the figure, the activated
S-LOIFLAP system is shown converting exogenous AA and IS-HpETE
to DiHETE and S,IS-DiHete, respectively.
Cover illustration and figures by Leigh Rondano with assistance from
Ann Hoffman, Carol Homon and Dr. Tom Parks, Boehringer Ingelheim
Pharmaceuticals, Inc.
Cover graphic design by David Gardner, Boston, MA.
The Search for
Anti-Inflammatory Drugs
Case Histories from Concept to Clinic
Vincent J. Merluzzi
Julian Adams
Editors
Birkhauser
Boston • Basel • Berlin
Vincent J. Merluzzi Julian Adams
Boehringer Ingelheim MyoGenics, Inc.
Pharmaceuticals, Inc. I Kendall Square, Bldg 200
900 Ridgebury Road Cambridge, MA 02139, USA
cr
Ridgefield, 06877, USA
Library of Congress Cataloging In-Publication Data
The Search for anti-inflammatory drugs: case histories from concept to clinic I
Vincent J. Merluzzi, Julian Adams, editors
p. cm.
Includes bibliographical references and index.
1. Anti-inflammatory agents--Reserach--History. I. Merluzzi, Vincent J.,
1949- ll. Adams, Julian, 1954-
[DNLM: 1. Anti-Inflammatory Agents. 2. Technology, Pharmaceutical--
history.]
QV 247 S439 1995 95-1583
615'.7--dc20 CIP
m®
Printed on acid-free paper
© 1995 Birkhiiuser Boston Birkhiiuser Il@
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ISBN-13: 978-1-4615-9848-0 e-ISBN-13: 978-1-4615-9846-6
DOl: 10.1007/978-1-4615-9846-6
Typeset by Martin Stock, Cambridge, MA
9 8 7 6 5 4 3 2 1
Contents
Preface ................................................ vii
Contributors ix
1 The Discovery of Drugs to Treat
Arthritis: A Historical View ............................ 1
Ivan G. Otterness
2 The History of the Discovery and
Development of Cyc1osporine (Sandimmune®) 27
IF. Borel, z.L. Kis, and T. Beveridge
3 Discovery and Development of FK506 (Tacrolimus),
A Potent Immunosuppressant of Microbial Origin ........... 65
Michihisa Nishiyama, Shizue Izumi, and Masakuni Okuhara
4 Discovery of Sulindac, a Reversible Prodrug,
as a Second-Generation Indomethacin .................... 105
Tsung Ying Shen
5 The Discovery of Zileuton (Leutrol®) 129
Dee W. Brooks and George W. Carter
6 Discovery of Accolate™ (ICI 204,219), a Peptide
Leukotriene Antagonist for Asthma ...................... 161
Frederick J. Brown
7 Discovery of ZD2138, a Potent, Selective, Well-Tolerated,
Nonredox Inhibitor of the Enzyme 5-Lipoxygenase ......... 191
G.c. Crawley, S.J. Foster, R.M. McMillan, and E.R.H. Walker
vi CONTENTS
8 Development ofMK 0591: An Orally Active
Leukotriene Biosynthesis Inhibitor with a
Novel Mechanism of Action ............................ 233
Petpiboon Prasit and Philip J. Vickers
9 Discovery of BIRM 270: A New Class of
Leukotriene Biosynthesis Inhibitors ...................... 253
Peter R. Farina, Carol Ann Homon, Edward S. Lazer, and
Thomas P. Parks
10 Discovery and Development of
the Immunomodulatory Azaspiranes ..................... 275
Alison M. Badger
Keyword Index ......................................... 303
Preface
Perspectives on Anti-Inflammatory Drugs
Inflammation is a very complicated process of interrelated events and cas
cades that does not allow for an easily defined, focused attack for drug
discovery. It is evident from years of research and development that certain
classes of compounds (e.g., NSAIDs, steroids, and so on) have had a meas
ure of success in alleviating pain and even dampening cellularlhormonal
mechanisms involved in the process. Clear, mechanism-related therapies
(e.g., for arthritis) and targeted drugs (e.g., for transplantation) have not
been available in the past and, in reality, research in inflammation has re
lied on more phenomenological approaches for resolving symptoms or on
blatant cytoreductive approaches in cases like organ transplantation.
In the last decade, approaches that have revealed novel cellular pathways
in which intervention is possible for lymphocyte regulation (for example,
cyclosporine and FK506) and small molecular weight mediators (e.g., leu
kotriene inhibitors) are now either standard therapy or will be in a short
time. These latter approaches have been the result of research from the
1970s up to the present.
The chapters in this book give a clear background on how some of these
current drugs were discovered and some of the problems and highlights that
took place in the development process. The chapters on cyclosporine and
FK506 provide a rich history of how these important chemical entities
were discovered and how they have made it on the long and arduous path
into the market place. They are classic examples of the first generation of
mechanism-related, immunosuppressive, anti-inflammatory drugs.
Inhibition of leukotrienes, either by direct enzyme inhibition, translo
cation, or antagonism at the level of the mediators, has been a focus for
the last ten to fifteen years as well. These inhibitors are currently reaching
the level of large clinical efficacy trials in asthma and other indications.
It has been a long journey for these compounds but nevertheless a fruitful
one to understanding these mediators, the mechanisms involved in their
viii PREFACE
synthesis, release, and ultimately in their biological effects. It is not sur
prising therefore to see a wealth of data on antagonism of these pathways.
These chapters, along with newer approaches (e.g., azaspirines), provide
interesting examples on the discovery of anti-inflammatory drugs.
The purpose of this book is to bring forward in both narrative and
technical format the true nature of the discovery and development process
for anti-inflammatory drugs. Ultimate success or failure in the clinic is not
the principle focus or issue here, but rather an understanding of the ways
concepts come into being and all of the thinking, nuance, and prejudice as
well as the scientific and political processes that come into play in drug
discovery. We hope that you will enjoy, as we have, the stories presented
in this book on the specific discovery and development of new chemical
entities.
The introductory chapter by Dr. Ivan Otterness sets the stage for the
following chapters. It presents the appropriate background and history to
the important but complicated field of research and development concern
ing arthritis. Arthritis is a disease with complex processes that ultimately
transgress all areas of inflammatory research. It is anticipated that over the
next decade we may be reading a similar treatise on events that have led to
new concepts in biotechnological products for inflammation, and perhaps
on small organic molecules whose mechanism of action is related to path
ways in cellular activation at the molecular level of gene expression. One
aspect that will probably remain constant, though, is the decision-making
that allows projects to go forward or retreat. We hope that this aspect of this
book will distinguish it from others that are usually collections of purely
technical articles.
Vincent Jay Merluzzi
Julian Adams
Spring 1995
Contributors
Alison M. Badger, SmithKline Beecham Pharmaceuticals, 709 Swedeland Road,
King of Prussia, PA 19406, USA
T. Beveridge, Department of Clinical Research, Sandoz Pharma Ltd., Lichtstrasse
35, CH-4002, Basel, Switzerland
Jean F. Borel, Department of Preclinical Research, Sandoz Pharma Ltd., Lichtstrasse
35, CH-4002, Basel, Switzerland
Dee W. Brooks, Immunoscience Research Area, Abbott Laboratories, D-47K, AP-
10, One Hundred Abbott Park Road, Abbott Park, IL 60064, USA
Frederick J. Brown, Department of Medicinal Chemistry, Zeneca Pharmaceuticals
Group, a business unit of Zeneca, Inc., 1800 Concord Pike, Wilmington, DE
19897, USA
George W. Carter, Immunoscience Research Area, Abbott Laboratories, D-462,
AP-9, One Hundred Abbott Park Road, Abbott Park, IL 60064, USA
G.c. Crawley, Zeneca Pharmaceuticals, Mereside, Alderley Park, Macclesfield,
Cheshire SKlO 4TG, England
Peter R. Farina, Department of Inflammatory Diseases, Boehringer Ingelheim Phar
maceuticals, Inc., 900 Ridgebury Road, P.O. Box 368, Ridgefield, CT 06877,
USA
S.J. Foster, Zeneca Pharmaceuticals, Mereside, Alderley Park, Macclesfield, Che
shire SKlO 4TG, England
Carol Ann Homon, Department of Inflammatory Diseases, Boehringer Ingelheim
Pharmaceuticals, Inc., 900 Ridgebury Road, P.O. Box 368, Ridgefield, CT
06877, USA
Shizue Izumi, Department of Pharmacology, Pharmacological Research Laborato
ries, Fujisawa Pharmaceutical Co., Ltd., 2-1-6, Kashima, Yodogawa-ku, Osaka,
Japan
ZL. Kis, Department of Preclinical Research, Sandoz Pharma Ltd., Lichtstrasse 35,
CH-4002, Basel, Switzerland
x CONTRIBUTORS
Edward S. Lazer, Department of Medicinal Chemistry, Boehringer Ingelbeim Phar
cr
maceuticals, Inc., 900 Ridgebury Road, P.O. Box 368, Ridgefield, 06877,
USA
R.M. McMillan, Vascular Inflammatory and Musculoskeletal Research Department,
Zeneca Pharmaceuticals, Mereside, Alderley Park, Macclesfield, Cheshire SKI 0
4TG, England
Michihisa Nishiyama, R&D Planning and Coordination, Fujisawa USA, Inc., Three
Parkway North, Deerfield, IL 60015-2548, USA
Masakuni Okuhara, Exploratory Research Laboratories, Fujisawa Pharmaceutical
Co., Ltd., 5-2-3, Tokodai, Tsukuba, Ibaraki, Japan
Ivan G. Otterness, Department of Immunology and Infectious Disease, Pfizer, Inc.,
cr
Central Research, 558 Eastern Point Road, Groton, 06340, USA
Thomas P. Parks, Department of Inflammatory Diseases, Boehringer Ingelheim
cr
Pharmaceuticals, Inc., 900 Ridgebury Road, P.O. Box 368, Ridgefield,
06877, USA
Petpiboon Prasit, Department of Medicinal Chemistry, Merck Frosst Centre for
Therapeutic Research, P.O. Box 1005, Pointe-Claire Dorval, Quebec H9R 4P8,
Canada
Tsung Ying Shen, Department of Chemistry, University of Virginia, McCormick
Road, Charlottesville, VA 22901, USA
Philip J. Vickers, Merck Frosst Centre for Therapeutic Research, P.O. Box 1005,
Pointe-Claire Dorval, Quebec H9R 4P8, Canada
E.R.H. Walker, Vascular Inflammatory and Musculoskeletal Research Department,
ZenecaPharmaceuticals, Mereside, Alderley Park, Macclesfield, Cheshire SKI 0
4TG, England