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Chapter • Drug Research: Yesterday, Today, and Tomorrow
1
The direct path to medicines is an old dream of mankind.
Even the alchemists searched for the elixir, the Arcanum,
that would cure all diseases. It has still not been found.
On the contrary, drug therapy has become even more
complicated as our knowledge of the various causes of
disease has become more complex.
Nevertheless, the success of drug research has been
impressive. For hundreds of years, alcohol, opium, and
solanaceous alkaloids (from thorn apples) were the only
drugs used to prepare for surgery. Today, general anesthesia, neuroleptanalgesia, and local anesthetics make surgical and dental procedures completely painless. Until this
century, plagues and infectious diseases killed more people than all the wars. Today, thanks to hygiene, vaccines,
chemotherapeutics, and antibiotics, these diseases have
been suppressed, at least in industrialized countries. The
dangerously increasing number of therapy-resistant bacterial and viral pathogens (e.g., tuberculosis) has created
new problems and makes the development of new drugs
urgently necessary. H2-receptor antagonists and proton
pump inhibitors have dramatically reduced the number
of surgical procedures for the treatment of gastric and
duodenal ulcers. Combinations of these inhibitors with
antibiotics have brought even more progress by allowing
causal therapy (Sect.3.5). Cardiovascular diseases, diabe-
tes, and psychiatric diseases (diseases of the central nervous system, CNS) are mostly treated symptomatically,
that is, the cause of the disease is not addressed, but rather
the negative effects of the disease on the organism. Treatment is often limited to slowing the progression of the disease or improving quality of life. Synthetic corticosteroids
have led to signicant pain reduction and retardation of
pathologic bone degeneration associated with chronic inammatory diseases (e.g., rheumatoid and chronic polyarthritis). The spectrum of cancer therapy ranges from cure,
especially in combination with surgery and radiotherapy,
to complete failure of all therapeutic measures.
Highlights such as inhibitors of BCR-ABL kinase
for ahereditary form of blood cancer are unfortunately
still the exception (Sect.26.4). Recent developments that
stimulate the body’s own immune system to ght cancer
are promising (Sect.31.7).
In the case of bacterial infectious diseases such as tuberculosis or viral diseases, the threatening increase in the
number of therapy-resistant pathogens is constantly creating new problems. Strongly modied viral variants can
suddenly become amassive threat. At the turn of the year
2019/2020, the world had to learn this the hard way. We
witnessed how the new highly contagious SARS-CoV-2
virus spread across the globe in the blink of an eye. Most
likely, the virus was transmitted to humans from apet
market in Wuhan, China, with bats and other animals
as intermediate hosts. But rumors that the outbreak was
caused by an accident or carelessness in ahigh-security
virus research laboratory added to the already tense, often politically motivated speculations. From continent to
continent, health systems were stretched to the limit and
sometimes hopelessly overwhelmed. Mankind experienced in all its severity what the exponential spread of avirus really means. Rapidly increasing numbers of victims
were terried country after country. Social and economic
life came to astandstill for weeks. Both acute medicine
and any kind of antiviral therapy seemed overwhelmed.
Nothing but the robustness of one’s own immune system had the power to counteract the virus. What sounds
like ahorror scenario in an apocalyptic novel suddenly
became reality. The World Health Organization (WHO)
reports that by 2024, 777million people worldwide had
been infected with the virus and 7.1million had died from
the infection. This bitter experience alone is apainful reminder of the urgent need to develop new medicines and
therapies. This is especially true if we want to maintain
the quality of life that we have already achieved. The mutability of some viruses and the fact that they can easily
jump between animals and humans should be warning
enough. It seems almost miraculous that apandemic
like the one in 2020 has not happened before. Perhaps
the Spanish u of ahundred years ago was similar, with
ahighly pathogenic inuenza virus. This makes it all the
more likely that the pandemic we have now experienced
will not remain asingular event. As if by miracle, two
companies managed to develop highly effective mRNA
vaccines within just one year (Sect.32.4), which are now
offering protection to mankind. In the eld of protease
inhibitors, too, atherapeutic agent was made available in
record time (Sect.23.9). In the face of adversity, mankind
seems to be able to lower bureaucratic hurdles, at least for
ashort time. We are capable of extraordinary innovation
and results-oriented decision-making. In retrospect, this
was only possible because the scientic community had
years of experience in drug discovery. It would be desirable if this spirit from the pandemic era could be carried
over into future research to combat cancer and neglected
infectious diseases.
The history of drug discovery can be divided into sev-
eral sequential phases:
The beginning, when empirical methods were the only
-
source of new medicines,
Targeted isolation of active compounds from plants,
-
The beginning of asystematic search for new syn-
-
thetic materials with biological effects and the introduction of animal models as surrogates for patients,
The use of molecular and other in vitro test systems
-
as precise models and as areplacement for animal
experiments,
The introduction of experimental and theoretical
-
methods such as protein crystallography, molecular
modeling, and quantitative structure–activity relationships for the targeted structure-based and computer-aided design of drugs, and
The discoveries of new targets and the validation of
-
their therapeutic value through genomic, transcrip-
. • It All Began with Traditional Medicines
tomic, and proteomic analysis, knock-in and knock-
out animal models, and gene silencing with siRNA.
Each preceding phase loses its importance as the next
phase arrives. Interestingly, in modern drug discovery,
the phases run in the opposite direction. First, atarget
structure is discovered in the sequenced genome of an
organism and its function is modulated to validate this
target as acandidate for drug therapy. This is followed
by structure-based and computational design of acompound in close collaboration with multiple in vitro assays
to elucidate the activity and spectrum of activity. The
next step is animal testing to establish clinical relevance,
and nally clinical trials to conrm the suitability of
atest substance as amedicine for patients.
1.1 It All Began with Traditional
Medicines
The beginnings of drug therapy can be found in traditional medicine. The narcotic effect of poppy milk, the
use of autumn crocus (Colchicum autumnale) for gout,
and the diuretic effect of squill (Urginia maritime) for
dropsy (now called congestive heart failure) have been
known since ancient times. The dried herbs and extracts
of these and other plants have been amajor source of
medicine for more than 5000 years. The oldest written
records of their use date back to 3000 BCE.
Around 1550 BCE, the ancient Egyptian Papyrus
Ebers listed about 800 prescriptions, many of which included additional rituals to invoke the help of the gods.
The ve-volume book De Materia Medica by Dioskurides (Greek physician, rst century CE) is the most
scientically rigorous work of antiquity. It contains descriptions of 800 medicinal plants, 100 animal products,
and 90minerals. Its inuence extended into late Arabic
medicine and early modern times.
The most famous medicine of antiquity was undoubtedly theriac. Its predecessor, mithridatum, was used by
the king of Pontus, MithridatesVI (120–63 BCE), as
an antidote for poisonings of all kinds. Theriac can be
traced back to Andromachus, the private physician of the
Emperor Nero, and originally contained 64ingredients.
This preparation was widely used until the eighteenth
century. It was prepared in many variations with up to
100 ingredients. In some cities, it was even prepared under state control to ensure that no ingredient was left out!
Its use became apanacea for all diseases. In addition, every imaginable wonder drug was used; some examples are
rain worm oil, unicorn powder, stomach stones, human
cranium powder, mummy dust, and many more.
Traditional Chinese medicine was already very advanced in ancient times. Apeculiarity of its formulation
was and is the circumstances responsible for the effect of
four different qualities. The chief (jun) is the carrier of the
effect, the adjutant (chen) supports the effect or induces
another effect. The assistant (zuo) may also support the
main effect or serve to ameliorate side effects, and one or
. Fig. 1.1 Many important natural products were isolated in the nine-
teenth century, and afew were synthesized. Morphine1.1 was isolated
from opium by Friedrich Wilhelm Adam Sertürner in 1806, caffeine1.2
was isolated from coffee, and quinine1.3 was isolated from cinchona
bark by Friedlieb Runge in 1819. Quinine was discovered independently
by Pierre Joseph Pelletier and Joseph Bienaimé Caventou, who one year
later isolated colchicine1.4 from autumn crocus. Cocaine1.5 was ex-
tracted from coca leaves by Albert Niemann in 1860, and ephedrine1.6
was extracted from the Chinese plant Ma Huang (Ephedra vulgaris) by
Nagayoshi Nagai. In 1886, the rst alkaloid, coniine1.7, which is found
in hemlock, was synthesized by Albert Ladenburg; in 1901 atropine1.8
was synthesized from deadly nightshade by Richard Willstätter. Reserpine1.9 from Rauwola serpentina was rst prepared in the middle of
the twentieth century, and its structure was elucidated
Chapter • Drug Research: Yesterday, Today, and Tomorrow
1
more messengers (shi) moderate the desired effect. The
Chinese Pen-Ts’ao school (rst and second century CE),
whose goal was to live as long as possible without aging
(!), recommended the following dosage regimen:
“When treating adisease with amedicine, if astrong ef-
»
fect is desired, one should begin with adose that is not
larger than agrain of millet. If the disease is healed,
no more medicine should be given. If the disease is not
healed, the dose should be doubled. If that does not heal
the disease, the dose should be increased tenfold. When
the disease is healed, the therapy should always be discontinued.”
The Chinese Materia Medica, published by Li Shizhen
in 1590, consists of 52volumes. It contains nearly 1900
medical principles, plants, insects, animals, and minerals, with 10,000 detailed recipes for their preparation.
The Chinese Pharmacopeia of 1990 contains only two
volumes. One of these volumes contains 784 traditional
medicines, while the other contains 967 medicines from
“Western” medicine.
Paracelsus (born Theophrastus Bombastus von Hohenheim; 1493/1494–1541) made agreat breakthrough
for scientic medical research. He understood the human
body as a“chemical laboratory” and held the ingredients
of medicines themselves, the Quinta Essentia, responsible
for their healing effects. Nevertheless, until the beginning
of the nineteenth century, all therapeutic principles were
based on either plant, animal, or mineral extracts; only in
the rarest cases were pure organic compounds used. This
changed radically with the advent of organic chemistry.
The great age of natural products from plants (for examples see 1.1–1.9, . Fig.1.1) and the active substances
derived from them had begun. Premature hopes placed in
some of these substances at the turn of the last century,
for example in heroin (Sect.3.3) or cocaine (Sect. 3.4),
were very quickly dashed, but natural products from
plants laid the foundation for our modern pharmacy and
form an exceedingly large part of it. Natural products
and their analogues and derivatives are also well represented among today’s best-selling drugs.
1.2 Animal Experiments as aStarting
Point for Drug Research
The wealth of experience of traditional medicine is based
on many thousands of years of sometimes accidental,
sometimes intentional observations of their therapeutic effects on humans. Planned studies on animals were
relatively rare. The biophysical experiment of Luigi Galvani, aprofessor of anatomy in Bologna, rst described
in his book De viribus electricitatis in motu musculari in
1791, has become famous. As early as 1780, his students
had observed frog legs twitching when the nerve was dissected while astatic electricity generator was used. Such
devices were standard equipment in many laboratories at
the time. He wanted to show in standardized experiments
whether the twitching was also caused by thunderstorms.
He hung the legs on an iron window grill with acopper hook—they twitched already when they touched the
grill. The voltage difference between the two metals was
enough to stimulate the nerve, even without an electrical
discharge.
The systematic study of the biological effects of plant
extracts, animal venoms, and synthetic substances on animals began in the mid-1800s. In 1847, the rst department
of pharmacology was established at the Imperial University in Dorpat (today Tartu, Estonia). The famous pharmacologist Sir JamesW. Black, who developed the rst
β
-blocker (an antihypertensive drug, Sect.29.3) at ICI and
later helped develop the rst H2 antagonists (see gastrointestinal ulcer drugs, Sect.3.5) at Smith, Kline & French,
compared pharmacological testing to aprism: what pharmacologists see in the properties of their substances depends directly on the model used to test the substances.
Like aprism, the models distort our vision in different ways. There is no such thing as adepressed rabbit or
aschizophrenic rat. Even if such animals existed, they
would not be able to share their subjective perceptions
and emotions with us. Genetically modied animals
(Sect.12.5), such as the Alzheimer mouse, are also approximations of reality that have been distorted through
adifferent prism, to use Black’s analogy. This reality is
often underestimated in industrial practice. Scientists
tend to optimize their experiments on aparticular, isolated model. In doing so, many factors and characteristics that are essential for adrug, such as selectivity or
bioavailability, are not sufciently taken into account.
There is no way out of this dilemma. We need simple
in vitro models (Sect.1.5) to test large series of poten-
tially active compounds, and we need the animal models
to correlate the data and make predictions about therapeutic effects in humans. Historically, therapeutic advances have been made when anew in vivo or in vitro
pharmacological model was available for anew effect (see
H2-receptor antagonists, Sect.3.5).
Typical errors in the selection of models and in the
interpretation and comparison of experimental results
arise from different modes of application and the correlation of results obtained in different animal species.
It does not make sense to optimize the therapeutic range
of acompound in one species and the toxicology in another. Furthermore, comparing effects after axed dose
without determining an effective dose also distorts the
results because very potent and weak substances fall outside the measurement range. Measuring the effect strictly
according to aschedule is also questionable because it
does not capture the latency period, the time before an
. • Biological Concepts in Drug Research
effect is seen, nor the time of maximum biological effect.
Whole-animal models usually involve the use of auxiliary medications, which can also inuence experimental
results. Anesthetized animals often give completely different results than conscious animals.
1.3 The Battle Against Infectious Disease
Plague and infectious diseases, most notably malaria and
tuberculosis, have killed more people over time than all
the wars in human history. Twenty-two million people
died in the rst wave of the 1918 inuenza (“Spanish
u”). Until the middle of the twentieth century, millions
of people died each year from malaria, and unfortunately
these numbers are rising again today (Sect.3.2). Until the
turn of the century, ipecac (Psychotria ipecacuanha) and
cinchona (Cinchona ofcinalisL.) were the only therapeutic approaches to this disease. The impressive successes
in the ght against the plague are largely due to the last
80years of drug research. We owe this to the sulfonamides
(Sect.2.3) and their combinations with dihydrofolate reductase inhibitors (Sect.27.2), the antibiotics (Sects.2.4,
6.4, and32.7), and the synthetic tuberculostatic drugs
(Sect.6.5). When SelmanA. Waksman (1888–1973) received the Nobel Prize for the discovery of streptomycin
(Sect.6.4), alittle girl congratulated him with abouquet
of owers. She was the rst patient with meningeal tuberculosis to be healed with streptomycin. Today we cannot
imagine the atmosphere of atuberculosis hospital from
our own experience, but only from Thomas Mann’s The
Magic Mountain (German: Zauberberg).
But infectious diseases, including tuberculosis, are
on the rise. In the past, many antibiotics were overused.
This, combined with the spread of resistant pathogens in
hospitals, means that many cases can only be treated with
very specic antibiotics. If resistance develops to these
antibiotics, all our weapons will be blunt. New viral infections are on the horizon. Before the advent of acquired
immune deciency syndrome (AIDS), there were very few
cases of pneumonia caused by the fungus Pneumocystis
jirovecii (formerly Pneumocystis carinii). This type of
pneumonia is the main cause of death in AIDS patients
and immunosuppressed patients after organ transplantation. Great efforts have been made to nd drugs to treat
AIDS and its complications (Sect.24.3). On the other
hand, many widespread tropical diseases, such as malaria
and Chagas disease, are still inadequately researched,
and the spread of resistance to currently available drugs
is agrowing global problem. Because these diseases are
rampant in parts of the world where people lack the economic resources to afford chemotherapy, more and more
pharmaceutical companies have withdrawn from these
areas of research for economic reasons. The chances of
recovering the development costs from the population
of the Third World are poor. This is where global policy must provide some structure so that these people can
benet from the technological advances of modern drug
research. One example of this is the Bill and Melinda
Gates Foundation, which is dedicated to the treatment
and eradication of diseases throughout the world, with
aparticular focus on developing countries. Improved hygiene has also helped reduce the risk of infections such
as traumatic fever and Shigella dysentery (discussed in
Chap.21). Above all, vaccines have contributed to the
eradication of many infectious diseases. Hopes are still
pinned on new and combined vaccines for the prevention
of AIDS, malaria, and gastrointestinal ulcers, the latter
now known to be caused by the bacterium Helicobacter
pylori (Sect.3.5). The Coronavirus pandemic in 2020 has
made us once again aware of the importance of developing avaccine in time to immunize the population.
1.4 Biological Concepts in Drug Research
Acetylcholine 1.10 (. Fig.1.2), synthesized by Adolf
v.Bayer in 1869, is aneurotransmitter, that is, a transmitter of nerve impulses. In 1921, Otto Loewi, apharmacologist, demonstrated its biological action in an elegant
experiment. Two isolated frog hearts were perfused with
the same solution. The vagal nerve of one of the hearts
was stimulated, resulting in aslowing of the heart rate,
known as bradycardia. Shortly thereafter, the second
heart also began to beat more slowly, aclear indication
of humoral signaling. Soon after, acetylcholine was identied as the responsible “vagus substance.” Acetylcholine
itself cannot be used therapeutically because it is metabolized too quickly by acetylcholine esterases (Sect.23.7).
In 1901, Thomas Bell Aldrich (1861–1938) and Jok-
ichi Takamine isolated the rst human hormone, adrenaline (also called epinephrine) 1.11 (. Fig. 1.2). This
hormone and its N-desmethyl derivative, noradrenaline
(also called norepinephrine) 1.12, are produced in acentral location, the adrenal glands, and are released under
stress conditions to the entire system except the CNS and
placenta, which have their own barriers to most polar
compounds. These substances cause different reactions
in different parts of the organism, where they react with
the corresponding receptors. The specicity is poor, and
aplethora of pharmacodynamic effects result: pulse and
blood pressure rise, and the organism is prepared for
“ight”—which has been an extremely important function throughout evolution.
Noradrenaline and adrenaline are neurotransmit-
ters (Sect.29.3), as are acetylcholine, biogenic amines
1.13–1.15, amino acids 1.16–1.19, and peptides such as
1.20 and 1.21 (. Fig.1.2). Neurotransmitters are pro-
duced locally in nerve cells, stored, and released upon
nerve stimulation. After interacting with receptors on the
Chapter • Drug Research: Yesterday, Today, and Tomorrow
1
. Fig. 1.2 The natural hormones und neurotransmitters acetylcho-
line 1.10, adrenaline 1.11, noradrenaline 1.12, dopamine 1.13, histamine 1.14, and serotonin 1.15, the excitatory amino acids glutamic
acid 1.16 and aspartic acid 1.17, the inhibitory amino acid glycine 1.18
and γ-aminobutyric acid (GABA) 1.19, and several peptides, such as
the enkephalins 1.20 and 1.21, substanceP and others serve as lead
structures for drugs for avariety of cardiovascular and CNS diseases
(see Chaps.3,29, and30)
neighboring nerve cell, they are rapidly metabolized or
taken up again by the same neuron that released them.
Depending on the name of the neurotransmitter, we
speak of the adrenergic, cholinergic, and dopaminer
gic (etc.) systems. The effect produced by adrenaline is
called adrenergic, and an antagonist of this system is
called anti adrenergic. However, this nomenclature is not
always strictly observed. It is common to see combinations of the name of the neurotransmitter with the term
agonist or antagonist, or sometimes blocker instead of
antagonist, for example, adopamine agonist, ahistamine
antagonist, or aβ-blocker for antagonists of β-adrenergic
receptors (Sect.29.3). Aplethora of drugs have been derived from the structural variations of neurotransmitters.
At the end of the 1920s, the steroid hormones were
isolated and their structures determined (Sect. 28.5).
Overall, the discoveries of the mid-twentieth century
heralded the “golden age” of drug discovery. The systematic variation of the principles responsible for biological
activity and our increasing knowledge of the mode of
action led to the synthesis of enzyme inhibitors, receptor
agonists and antagonists, which, together with natural
product derivatives from plants, make up the majority
of our modern pharmacopeia.
1.5 In Vitro Models and Molecular Test
Systems
About 50years ago, we started thinking about testing
compounds in simple in vitro models. These models involve biological testing in test tubes rather than on animals. There are many compelling reasons to avoid ani-
mal testing. They are increasingly criticized by the public
for many good reasons. They are also time consuming,
costly, and difcult to standardize. Initially, cell culture
models were preferred, such as tumor cell cultures for
testing cytostatic therapies or embryonic chicken heart
cells for testing cardiac agents. Later, receptor binding
studies were added. The rst molecular test models were
enzyme inhibitor assays, in which the inhibitory activity
of amolecule on aspecic target protein could be evaluated in the absence of disturbing side effects (Chap.7).
Advances in gene technology (Chap.12) have not only
simplied the preparation of the enzyme, but also allowed receptor binding studies to be performed on standardized materials. It is now possible to accurately evaluate the full spectrum of activity of any compound on any
enzyme, receptor of any type or subtype, ion channel, or
transporter. This has become routine in academic and
industrial drug discovery. Before biological screening begins, the following questions must be answered: What is
the therapeutic target to be addressed and how can it be
achieved? Therapeutic concepts are based on the pathophysiology and the causes of its alteration. Regulatory
interventions with drugs are intended to restore normal
physiological conditions as closely as possible. But there
is aproblem. Nature works on two orthogonal principles:
the specicity of the mode of action and an accentuated
-
spatial separation of effects; the compartmentalization.
Adrenaline, produced in the adrenal glands, affects the
entire body except the brain. When it is released there, it
acts only at the synapse between two nerve cells. When
it comes to specicity, chemists can beat Nature most of
the time, but when it comes to spatial separation, they
fail by awide margin.
Advances in gene technology (Chap.12) allow us to
study compounds much more precisely than in the past,
but the use of isolated enzymes and binding studies is far
from the reality of animal models and even further from
humans. In analogy to the difference between an animal
experiment and an isolated organ experiment, awell-established correlation between the results obtained in cell
culture and an in vitro assay and the desired therapeutic
effect is aprerequisite for the successful use of the in
vitro model. Quantitative activity-activity relationships
. • The Successful Therapy of Psychiatric Illness
between different biological effects (Chap. 19) provide
the link between animal models and humans.
One modern researcher stands out in the eld of CNS
drugs, but also in the elds of cardiovascular drugs and
antihistamines. Paul Janssen (1926–2003) was the director of Janssen Pharmaceuticals in Beerse, Belgium. In the
years following World WarII, his company discovered
more than 70new compounds, took them through preclinical and clinical development, and established them
as therapeutics. In the process, his company established
itself as the most successful in pharmaceutical history.
His recipe for success was no secret. Paul Janssen was
amaster of structural variation, a“Beethoven of drug
discovery.” The systematic combination of pharmacologically interesting structural building blocks and the
elegant evaluation of receptor binding studies, in vitro
models, and animal experiments were the basis of his
success.
1.6 The Successful Therapy of Psychiatric
Illness
Until the middle of the last century, psychiatric hospitals were purely custodial institutions; they were almost
indistinguishable from prisons in terms of restricting an
individual’s personal freedom. The discovery of neuroleptics, antidepressants, anticonvulsants, and sedatives
revolutionized psychiatry. Typical examples of this class
of drugs are shown in . Fig.1.3. With the repertoire
of drugs available today, schizophrenia, chronic anxiety, and depression preponderate open-ward psychiatry.
Many patients can be treated in an ambulatory setting.
In 1933, Manfred Sakel (1901–1957), who worked at
the Psychiatric University Hospital in Vienna, noticed
that individuals with schizophrenia who were given insulin to stimulate their appetite became calmer. Encouraged by this result, he increased the dose to the point
of hypoglycemic coma, aform of deep unconsciousness
induced by low blood sugar. Insulin shock, pentetrazole, and electroshock became standard treatment for
psychotic illness for the next two decades, an impressive
and frightening demonstration of the lack of therapeutic
alternatives.
This situation changed in the 1950s with the discovery
of reserpine1.9 (. Fig.1.1), an herbal natural product.
This substance acts by depleting the reserves of the neurotransmitters noradrenaline, serotonin, and dopamine
in nerve cells. Reserpine was the rst substance to show
apronounced neuroleptic effect, that is, it is sedating
and calming, and it was the rst compound used in psychotic disorders for which the biological effect could be
explained by amode of action. Reserpine has also been
used as an antihypertensive drug. Because of its very
broad and unspecic action, it is rarely used today for
psychiatric disorders or arterial hypertension.
. Fig. 1.3 A revolution in the therapy of psychiatric illness was
brought about by the discovery of potent neuroleptics such as chlorpromazine 1.22, tranquilizers such as diazepam 1.23, and antidepressants such as imipramine 1.24. For the rst time, these compounds
allowed targeted treatment of schizophrenia, chronic anxiety, and
depression. Examples of newer antidepressants with specic modes
of action on transport systems (Sect.22.7) for noradrenaline and serotonin are desipramine 1.25 and uoxetine 1.26, respectively
The role of dopamine 1.13 (. Fig.1.2) in the etiol-
ogy of schizophrenia became clear with the discovery
of chlorpromazine 1.22 (. Fig.1.3), asubstance that
showed afavorable clinical effect. Unlike reserpine, which
is nonspecic, chlorpromazine is apure dopamine antagonist. The use of chlorpromazine and analogous tricyclic
neuroleptics induced symptoms similar to those seen in
Parkinson’s disease. This was the rst indication that an
endogenous dopamine deciency was the cause of this
disease.
Chlordiazepoxide (Librium®, Sect.2.7), the rst ben-
zodiazepine tranquilizer, was discovered by chance. Only
ayear after its introduction and for many years after
that, the chemically closely related drug diazepam 1.23
(Valium®, . Fig.1.3) was the world’s best-selling drug.
The Rolling Stones commemorated it in their multifaceted song “Mother’s Little Helper.” Many companies
embarked on elaborate synthetic programs, and chemists and pharmacologists applied their entire arsenal of
methods. Success justied their efforts. Substances with
different modes of action were created: more tranquilizers, sedatives, hypnotics, and even antagonists. Even
today, benzodiazepines (Sect.30.7) are among the most
popular and widely used drugs.
The rst antidepressant, iproniazid (Sect.27.8), was
also an accidental discovery. It works by inhibiting the
metabolism of the biogenic amines dopamine, serotonin,
noradrenaline, and adrenaline by inhibiting the enzyme
monoamine oxidase (Sect.27.8). In addition to other
Chapter • Drug Research: Yesterday, Today, and Tomorrow
1
severe side effects, the rst nonspecic representatives
caused hypertensive crises and, when taken with certain
foods, afew fatalities occurred. Tyramine, asubstance
found in cheese, wine, and beer (hence the term “cheese
effect”), was not properly metabolized. This caused
alife-threatening increase in noradrenaline, ahormone
that raises blood pressure.
The antidepressant imipramine 1.24 (. Fig.1.3) re-
sulted from the synthesis of analogues of chlorpromazine. Interestingly, and despite its close structural relationship, it is not aneuroleptic, but rather acts in the
opposite way. It blocks the transporter for noradrenaline
and serotonin (Sect.30.10), thus, preventing the re-uptake of these neurotransmitters from the synaptic gap.
Desipramine 1.25 and uoxetine 1.26 are even more
selective in that they inhibit only the noradrenaline or
serotonin transporter of nerve cells.
1.7 Modeling and Computer-Aided
Design
To model the properties and reactions of molecules, and
especially their intermolecular interactions, apowerful
tool is available: the computer. In addition to solving complex numerical problems, it is the translation of the results
into color graphics that perfectly matches the human abil-
ity to comprehend images more quickly and easily than
text or columns of numbers. This is not surprising. Our
brains process text sequentially, but images are grasped in
parallel. X-ray crystallography, electron microscopy, and
multidimensional NMR spectroscopy (Chap.13) contribute to our understanding of molecules, as do quantum
mechanical and force eld calculations (Chap.15).
Is molecular modeling an invention of modern times?
Yes and no. Friedrich August Kekulé (1829–1896) is said
to have derived his cyclic structure for benzene from avision of asnake circling around itself and biting its own
tail (the snake, Uroborus, is an ancient alchemical symbol). The dream that became famous, however, may have
come from the memory of the book Constitutionsformeln
der Organischen Chemie by the Austrian schoolteacher
Joseph Loschmidt (1821–1895; . Fig.1.4). The notation
for the constitution of organic compounds introduced
by Kekulé has become widely accepted and has greatly
stimulated organic chemistry. However, Loschmidt
would have been pleased to see images from molecular
modeling that closely resemble his formulas. Today, we
are increasingly focusing on the three-dimensional character, steric requirements, and electronic properties of
molecules. The rst structure-based design was performed
on hemoglobin, the red blood pigment, in the research
group of Peter Goodford (Sect.20.1). Hemoglobin’s afnity for oxygen is modulated by so-called allosteric effector molecules that bind to the core of the tetrameric
. Fig. 1.4 Loschmidt’s book Constitutionsformeln der Organischen
Chemie (1861) contains structures that anticipate both the formulation
of the benzene ring as well as the modern modeling structure. Kekulé
must have known about this book because he disparaged it in aletter
to Emil Erlenmeyer in January 1862 in that he referred to it as Con-
fusionsformeln. Loschmidt did not become famous for his book, but
rather because he carried out an experiment in 1865 that determined
the number of molecules in amole to be 6.02 × 1023, aconstant that
was later named after him
protein. From the three-dimensional structure, Goodford
deduced simple dialdehydes and their bisulte addition
products. These substances bind to hemoglobin in the
predicted manner and shift the oxygen-binding curve in
the expected direction.
The rst drug developed by using astructure-based
approach is the antihypertensive agent captopril,
an angiotensin-converting enzyme (ACE) inhibitor
(Sect.25.4). Although the lead structure was asnake
venom, the decisive breakthrough was made after modeling the binding site. For this, the binding site of carboxypeptidase, another zinc protease, was used because
its three-dimensional structure was known at the time.
The road to a new drug is difcult and tedious.
Anested overview of the interplay between the different
methods and disciplines from amodern point of view
is illustrated in the scheme in . Fig.1.5. In the last few
years, molecular modeling (Chap.15) and particularly
the modeling of ligand–receptor interactions (Chap.4)
have gained importance. Although modeling is employed
predominantly for the targeted structure modication of
lead compounds, it is also suitable for the structure-based
and computer-aided design of drugs (Chap.20) and lead
structure discovery (Sect.7.6). Examples of these approaches are given in Chaps.21,23–32.
In addition to modeling and computer-aided design,
structure–activity relationship analysis (Chap. 18) has
contributed to the understanding of the correlation between the chemical structure of compounds and their biological effects. By using these methods, the inuence of
lipophilic, electronic, and steric factors on the variation
. • The Results of Drug Research and the Drug Market
. Fig. 1.5 The way to a drug is long. The upper part of the gure
shows routes to lead structures. The middle part describes the design
cycle, which in practically all cases must be repeatedly re-iterated. Each
of these phases is described in detail in the following chapters. Iterative
of the biological activity, transport, and distribution of
drugs in biological systems could be systematized for the
rst time on statistically signicant foundations.
1.8 The Results of Drug Research
and the Drug Market
The development of different methods in drug research has
already been described in the last section. . Table1.1 gives
ashort historical overview of the most prominent results.
The assessment of a drug’s efcacy and safety has
reached an extraordinarily high level today. In some
ways, this has been abenet to our goal of nding new
medicines, but it has also been an obstacle. Acetylsalicylic
acid (Aspirin®) is undoubtedly avaluable drug. Today,
this compound would have great difculty passing clinical trials. Acetylsalicylic acid is an irreversible enzyme
inhibitor, it is relatively weakly effective, it causes gastric
optimization results in candidates for further development such as preclinical and toxicological studies. It is from these studies that the actual
candidates are selected. Formulation, clinical trials, and registration then
lead to anew medicine. The last phases are not presented in this book
bleeding at high doses, and it has avery short biological
half-life. Each of these problems would be astrong argument against its further development today. It would
probably have failed in screening. In arisk–benet analysis, however, it is better than most alternatives. What is the
problem? It probably lies in the analytical–deterministic
mindset that dominates science and, therefore, also drug
research. What is often overlooked is that such an approach cannot always do justice to the complexity of the
human system that we are dealing with in drug therapy.
Despite public healthcare systems that act as abarrier between the supplier and the consumer, the pharmaceutical market, with global sales of more than $1450
billion, is highly competitive. Two forces inuence this
market: the state of science and technology and the needs
of patients. Asmall number of drugs account for the
majority of sales. Constantly changing “hit lists” of the
best-selling drugs can be found on the internet. Due to
mergers of established pharmaceutical companies over
Chapter • Drug Research: Yesterday, Today, and Tomorrow
1
. Table 1.1 Important milestones in drug research
the last 30–40years, the market has shrunk to a small
number of “BigPharma” companies. It is often the case
that asingle drug can make or break acompany. Often
just two or three drugs account for more than 50% of
alarge company’s sales. Ahistorical example is Glaxo. It
went from mideld to the top with ranitidine. Astra experienced asimilar boom with omeprazole. Today, after
the merger with Zeneca, it is one of the biggest players
in the eld. Sankyo also had asingle drug, lovastatin,
that boosted sales. With its drugs sildenal (Viagra®) and
atorvastatin (Sortis®/Lipitor®), Pzer’s prots soared to
unimaginable heights.
Over the past three decades, we have seen an increasing concentration of pharmaceutical companies, with the
market becoming an oligopoly dominated by multinational corporations. Bear in mind that sales giants such as
GlaxoSmithKline (GSK), Novartis, Sano, Bayer, Bristol-Myers-Squibb or AstraZeneca were created by mergers only about 20years ago. Companies such as Pzer
and Roche have grown signicantly through acquisitions.
The importance of research for pharmaceutical companies is evident when one considers that typically 15–20%
of turnover is invested in this area. It is unclear whether
an equibilirium in the pharmaceutical market has been
reached or whether the landscape will continue to change.
In the meantime, many small start-up biotech companies
are shaking up the scene. Globalization is also playing its
part. In addition, countries that have not yet reached the
necessary level of development in their research are now
entering the market. Political circumstances and risky
dependencies, which are now viewed as problematic, will
also contribute to arethinking of these developments.
1.9 A Subject of Conflict:
Pharmaceuticals
Drugs are at the center of public interest. While for decades only the doctor, sometimes in consultation with
the pharmacist, prescribed the use of adrug, today’s patients, alarmed by publications in the lay press, by package inserts, or by more or less serious and well-researched
information on the internet, want to take control of the
administration of a drug or at least participate in the
decision-making process. Inuencers are increasingly
shaping opinion, and the use of articial intelligence may
make it more and more difcult to distinguish between
serious information and fake news.
An example illustrates the issues. Psychotropic drugs
have apowerful effect on personality and behavior. At
. • Synopsis
least since the introduction of Valium® (diazepam), these
drugs have been in the media spotlight. They are invaluable in the treatment of psychiatric disorders. On the
other hand, the risk of abuse and addiction is particularly
high. Some of these drugs are even used for self-medication without strict adherence to indication guidelines.
Fluoxetine 1.26 (Prozac®, . Fig.1.3) was introduced by
Eli Lilly in 1988 and brought about aclear advance in the
treatment of depression. There are now over ten popular
science books with controversial content on this one drug
alone. Peter Kramer’s book Listening to Prozac takes
agenerally sympathetic tone, claiming that depressed patients feel better and more “in harmony” with their personalities after treatment with uoxetine. This book was
on the New York Times bestseller list for over 21weeks.
Peter Breggin’s book Talking Back to Prozac polemically
criticized uoxetine, the company Eli Lilly, and the U.S.
Food and Drug Administration (FDA). Side effects, risks,
and especially the addictive potential were emphasized.
Both books contain correct statements, but both may lead
to the wrong conclusions. Prozac® is avaluable drug for
the treatment of clinically manifest depression; however,
for the treatment of mundane unhappiness or as ageneral
stimulant, it is adrug with many risks.
To conduct arisk–benet analysis of adrug, it is important to consider not only the desired effect, but also
the severity of the disease and the objective and subjective
side effects. In oncology, even severe side effects are often tolerated for the possibility of improving the patient’s
condition. If aterminal cancer patient is denied effective
pain management because of the risk of addiction, this
must be considered malpractice. On the other hand, many
people are reckless with highly potent medications. Misuse of antibiotics, faith in the almighty power of tranquilizers and antidepressants, or chronic use of analgesics
and laxatives can do more harm than good.
1.10 Synopsis
Drug research can be divided into several sequential
-
phases starting with empirical observations of the up-
take of natural products from food, the development
of in vitro test systems, increasing understanding of
structures and modes of action, to in vivo models and
gene technology.
It all started with traditional medicines. The rst pre-
-
scriptions date back to the ancient Egyptians and to
traditional Chinese medicine.
Paracelsus founded scientic medical research and
-
understood humans to be a“chemical laboratory.”
The ingredients of drugs were rst held responsible
for healing effects.
With the advent of organic chemistry, the rst thera-
-
peutic principles based on pure organic compounds
became available. The great age of natural products
from plants and their active ingredients began.
Systematic studies on animals began in the 19th cen-
-
tury can be seen as astarting point for drug research.
In vitro models are needed to test large series of potentially active compounds, but animal models are
required to correlate the data and make predictions
about the therapeutic effects in humans.
Our present life expectancy would not be possible
-
without the successful ght against infectious diseases. The broad application of antibiotics and the
spread of resistant pathogens, however, have led to
situations in which the best weapons against infectious diseases are becoming increasingly ineffective.
Research against widespread tropical diseases has
been neglected, and the currently increasing resistance to available medications represents aworldwide
problem.
The elucidation of biological concepts, pathways,
-
and regulatory cycles by endogenous compounds has
strongly stimulated drug research. Many developed
drugs have arisen from structural variations of neurotransmitters, hormones, steroids, or natural substrates.
Systematic substance testing began with the estab-
-
lishment of in vitro models that replaced biological testing on animals by assays in test tubes. Gene
technology has made it possible to prepare sufcient
amounts of pure proteins for testing.
The discovery of neuroleptics, antidepressants, an-
-
ticonvulsives, and sedatives has revolutionized the
treatment of psychiatric diseases.
Molecular modeling and computer-aided design along
-
with structural biology give access to rational con
siderations on drug action. The rst structure-based
design project was carried out on hemoglobin, and
the rst drug developed by using astructure-based
approach was the antihypertensive captopril.
The assessment of drug efcacy and safety has
-
reached an extraordinarily high standard today. The
worldwide drug market, with more 1450 billion US
dollars in sales per year, is large and highly competitive. Only afew drugs command alarge portion of
sales and determine the particular dynamics in the
market; the current tendency is corporate contraction
to fewer and bigger companies. Often a single drug
can make or break acompany.
Drugs remain in the focal point of public interest.
-
It is no longer the physician alone who inuences
the prescription of medication; multiple sources of
information have an impact and inform the patient.
Aproper risk–benet analysis of amedication, taking
into consideration not only the desired therapeutic
effect but also the severity of an illness, is needed.
-