Drugs Affecting the Respiratory System

390 Pages·1980·5.86 MB·English

by  Davis L. Temple

Drugs Affecting
the Respiratory System
In Drugs Affecting the Respiratory System; Temple, D.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1980.
In Drugs Affecting the Respiratory System; Temple, D.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1980.
Drugs Affecting
the Respiratory System
Davis L. Temple, Jr., EDITOR
Mead Johnson Pharmaceuticals
Based on a symposium sponsored by
the Division of Medicinal Chemistry
at the 175th Meeting of the
American Chemical Society,
Anaheim, California,
March 13-16, 1978.
ACS SYMPOSIUM SERIES 118
AMERICAN CHEMICAL SOCIETY
WASHINGTON, D.C. 1980
In Drugs Affecting the Respiratory System; Temple, D.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1980.
Library of Congress CIP Data
Drugs affecting the respiratory system.
(ACS symposium series; 118 ISSN 0097-6156)
Includes bibliographies and index.
1. Respiratory agents—Congresses. 2. Structures—
activity relationship (Pharmacology)—Congresses.
I. Temple, Davis L., 1943- . II. American Chemi
cal Society. Division of Medicinal Chemistry. III.
Series: American Chemical Society. ACS symposium
series; 118.
RM388.D78 615'.72 79-24958
ISBN 0-8412-0536-1 ASCMC8 118 1-396 1980
Copyright © 1980
American Chemical Society
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PRINTED IN THE UNITED STATES OF AMERICA
In Drugs Affecting the Respiratory System; Temple, D.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1980.
ACS Symposium Series
M. Joan Comstock, Series Editor
Advisory Board
David L. Allara W. Jeffrey Howe
Kenneth B. Bischoff James D. Idol, Jr.
Donald G. Crosby James P. Lodge
Donald D. Dollberg Leon Petrakis
Robert E. Feeney F. Sherwood Rowland
Jack Halpern Alan C. Sartorelli
Brian M. Harney Raymond B. Seymour
Robert A. Hofstader Gunter Zweig
In Drugs Affecting the Respiratory System; Temple, D.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1980.
FOREWORD
The ACS SYMPOSIUM SERIES was founded in 1974 to provide
a medium for publishing symposia quickly in book form. The
format of the Series parallels that of the continuing ADVANCES
IN CHEMISTRY SERIE
papers are not typese
mitted by the authors in camera-ready form. Papers are re
viewed under the supervision of the Editors with the assistance
of the Series Advisory Board and are selected to maintain the
integrity of the symposia; however, verbatim reproductions of
previously published papers are not accepted. Both reviews
and reports of research are acceptable since symposia may
embrace both types of presentation.
In Drugs Affecting the Respiratory System; Temple, D.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1980.
PREFACE
he importance of the lungs as effector organs of respiration cannot be
-1- denied. Respiration and life itself depend ultimately on absorption
of oxygen from the atmosphere and excretion of carbon dioxide through
pulmonary ventilation. Good health depends on the quality of this vital
system. Thus impairment of the respiratory system through loss of respi
ratory muscle function, increased airway resistance, decreased lung com
pliance, alveolar destruction, or physical obstruction leads to a general
loss of ones ability to function
are progressive and may ultimately prove fatal, whereas a mild case of
bronchial asthma may merely limit one's capacity to exercise. However,
in every untreated case of respiratory disease the quality of life invari
ably is lowered.
Respiratory disease may often be traced to an external source such
as an inhaled allergen, pathogen, particulate matter, chemical irritant, or
other, undefined material. Ideally, the resulting disease state would be
abolished by removing the suspect material from the environment; how
ever, often this is not possible. We are left then to define effective drugs
for the treatment of bronchial asthma, chronic bronchitis, chronic pul
monary emphysema, and a variety of other debilitating respiratory
diseases.
It is the purpose of this book to explore the contemporaiy develop
ment of drugs affecting the respiratory system and their application to
modern medicine. The volume is divided into two parts: mediator release
inhibitors, and bronchodilators and other pharmacodynamic agents. In
the introduction to the first section, the historical importance of the evo
lution of cromolyn sodium from the naturally occurring compound khellin
is discussed. These mediator release inhibitors are useful prophylactic
drugs for the treatment of asthma, and their development has provided
both a new avenue for therapy and a new direction for the medicinal
chemist. Extensive efforts to develop an orally active, more effective
cromolyn-like drug by much of the pharmaceutical industry resulted in
a plethora of promising compounds; many of these were poorly effective
in the clinic and subsequently abandoned. Fortunately a number of these
agents did perform well in human clinical studies and are now in ad
vanced study. Successes in this area have come as a result of a better
understanding of the biologic mechanisms of action of antiallergic agents
and the inherent limitations of animal screening methods used to select
ix
In Drugs Affecting the Respiratory System; Temple, D.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1980.
clinical candidates. The development of several of the more promising
compounds is described also. The significant chemistry and structure-
activity relationships that led to the selection of these compounds are
highlighted.
The final chapter in this section deals with oxatomide, an antiallergic
antihistamine. This agent may act by a different mechanism than the
cromolyn-related antiallergics or the classical antihistamines. Such com
pounds are clinically effective and seem to offer yet a new direction for
exploration.
The second part of "Drugs Affecting the Respiratory System" focuses
on drugs that not only may inhibit immunologically induced release of
mediators from target cells, but more importantly, that may inhibit the
consequences of mediator release. Such drugs include bronchodilators
and other pharmacodynami
part, the multipartite nature of asthma and respiratory disease in general
are discussed. This sets the stage for the following chapter in which
pathophysiologic derangements in chronic obstructive pulmonary dis
ease are discussed from a clinical point of view. The need for agents,
such as bronchodilators, for chronic disease therapy and the deficiencies
in existing therapy are well illustrated.
The following two chapters deal with the historical and contemporary
aspects of both adrenergic and theophylline-related bronchodilator drugs.
Several new structural types are considered that may indicate future
trends in these areas. The problems with theophylline therapy are well
documented and the need for improved agents of this class is empha
sized.
The last chapter of the book explores in depth an important new area
—prostanoid bronchodilator drugs. An extensive review of the chemistry
and structure-activity relationships of the prostaglandin bronchodilators
is presented for the first time and prospects for a useful clinical agent are
discussed.
In recent years drug research in the respiratory area has been at an
all-time high. Much of this work has stemmed from the discovery of
cromolyn sodium as a truly new therapeutic modality as well as from a
better appreciation of the pharmacodynamics of theophylline. Newer
agents such as prostaglandin bronchodilators are now being studied
extensively. One must feel that these extensive efforts will culminate in
the development of better therapy for the patient suffering from respira
tory disease.
Mead Johnson Pharmaceuticals DAVIS L. TEMPLE, JR.
Evansville, Indiana 47721
August 6, 1979
x
In Drugs Affecting the Respiratory System; Temple, D.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1980.
1
Introduction: Perspectives on Antiallergic Agents
H. F. HODSON
The Wellcome Research Laboratories, Langley Court,
Beckenham, Kent BR3 3BS, England
It is now more than ten years since Fisons, U.K. introduced
the compound Intal, cromoly sodium disodiu cromoglycat
it will be referred to
for the prophylaxis of asthma i man. This introductio caused
considerable excitement and activity in the rest of the pharm
aceutical industry as well as in academic medical circles. There
were several reasons for this interest but one of the most import
ant was that cromoglycate appeared to be a drug with a completely
novel mode of action in asthma therapy.
Intal; disodium cromoglycate
To see how novel this mode of action was we must briefly
consider the processes which are believed to be involved in
allergic asthma. The basis of the disease is thought to be an
immunological process. The asthmatic individual has become
sensitised to an external agent, or antigen, usually protein in
nature, such as house dust mite, pollen, feathers, animal scurf,
etc. by producing antibodies towards the antigen. When the
sensitised individual comes into contact with the antigen these
antibodies combine with the antigen and the formation of antigen
-antibody complexes is followed by the release of a number of
substances, collectively called mediators, which together are
responsible for the bronchospasm and other symptoms of an
asthmatic attack. Among these mediators are histamine, serotonin,
kinins, and the so-called SRS-A. SRS-A is an as yet chemically
uncharacterised substance,* although considerable effort has been
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© 1980 American Chemical Society
In Drugs Affecting the Respiratory System; Temple, D.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1980.
4 DRUGS AFFECTING THE RESPIRATORY SYSTEM
and is currently being spent, on attempts to elucidate its
structure; the initials stand for Slow Reacting Substance of
Anaphylaxis. Anaphylaxis is a general term covering the full set
of reactions which are triggered off by the mediators.
The sequence of events, then, is as follows. An individual
reacts to an external agent or antigen by producing antibodies.
These antibodies become attached to the membrane of specialised
cells, for example mast cells, which contain the mediators in
granules. Once these antibodies are formed and have become
attached to the mast cell membrane the individual has become
sensitised. On further contact with antigen, or challenge, the
antigen combines with the cell-bound antibody, the antigen-anti
body complex remaining attached to the cell. The next event is
release of the mediators from the cells by a process known as
degranulation. This is not a break-down of the cells but is an
active secretory process; degranulated mast cells are able to
regenerate themselves. Th
anaphylaxis or anaphylactic shock which in the case of asthma is
primarily a contraction of the smooth muscle of the bronchioles
which leads to bronchoconstriction. In addition the lining of
the bronchioles swells and mucous is secreted. These and
associated reactions combine to reduce the passage of air and lead
to the typical asthmatic reaction.
If we accept this sequence of events, then, we can see that
there are several points at which it is theoretically possible to
interfere with the process and thereby to prevent or relieve an
asthmatic attack. The first point is the end organ, the
bronchioles. Before cromoglycate was introduced the most widely
used therapy in asthma employed bronchodilators, in the form of
3-adrenergic agents. These physiological antagonists act at the
final stage of the process by relaxing the smooth muscle of
bronchioles and thus counteracting the bronchoconstrictor effect
of the allergic mediators. However, in general 3-adrenergic
stimulants have poor selectivity of action. In particular they
have effects on the cardiovascular system, particularly the heart.
A second possible point of attack is not at the end organ
but on the mediators themselves, by the use of competitive ant
agonists. In this case, of course, we would need either an agent
which antagonised all the mediators or a mixture of agents, each
one antagonising one or more mediators. Antihistamines have
never been widely used in the clinical treatment of allergic
asthma suggesting that histamine does not play a dominant role in
this disease in man, although it is certainly important in ana
phylactic reactions in other species. There is, though, a great
deal of indirect evidence to show that SRS-A does play an import
ant role in inducing the symptoms of human allergic asthma. A
specific antagonist of SRS-A could therefore be of therapeutic
value in asthma and could also help to define the role of SRS-A in
asthma. The first such specific antagonist, FPL 55712, was
reported by Fisons, some four years ago but there have been no
In Drugs Affecting the Respiratory System; Temple, D.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1980.