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3
Chapter • Classical Drug Research
The 100years of pharmaceutical research from 1880
to 1980 were punctuated by trial and error, but also by
elegant ideas and their translation into therapeutically
valuable principles. Many lead structures were found by
accident (see Chap.2), while others came from traditional medicines or from biochemical concepts. In contrast to modern drug research, classical design was the
result of rather limited knowledge of the pathophysiology and cellular and molecular etiology of disease, and it
was restricted to animal testing. Nevertheless, this phase
was extremely successful, especially in its last 50years
until about 1980. The targeted ght against infectious
diseases and the successful treatment of many psychiatric
and other important diseases can be attributed to this
period of drug development. With this came asigni
cant increase in quality of life and life expectancy. In the
following sections, some selected examples are used to
demonstrate different aspects of classical pharmaceutical
research. They show how for known drugs, the eld of
application can expand over the years or how the therapy
in an indication area can change through the discovery
of new targets. The treatment of malaria illustrates that
the development of resistance forces the constant search
for new active substances with novel modes of action.
3.1 Aspirin: ANever-Ending Story
The history of acetylsalicylic acid (ASA, Aspirin®) reects the progress of pharmaceutical research like no
other example. This is especially true for the elucidation
of the mode of action, and the newly found targeted
therapies that resulted. Willow bark extracts have been
used since antiquity for the treatment of inammation.
When Napoleon marched across Europe between 1806
and 1813, the bark was even used as asubstitute for cinchona bark (Sect.3.2). Salicin3.1, a glucoside of the
o-hydroxybenzylalcohol saligenin, is responsible for the
effect. Upon hydrolysis and oxidation, the actual active
compound, salicylic acid3.2 (. Fig.3.1), is formed.
In 1897, the then 29-year-old Bayer chemist Felix
Hoffmann began asystematic search for derivatives of
salicylic acid after arequest from his father, who suffered
from severe rheumatoid arthritis. High doses of salicylic
acid caused unpleasant gastric irritation and vomiting.
Hoffmann prepared simple derivatives of salicylic acid
and was successful within the year. On October10, 1897,
he synthesized acetylsalicylic acid3.3 (ASA, . Fig.3.1)
for the rst time in apure form.
It was alucky strike. Although ASA has avery short
half-life in plasma, it is ahighly analgesic, antipyretic,
and anti-inammatory agent. The clinical trial was carried out at the Diakonissenkrankenhaus in Halle an der
Saale on 50patients. On February1, 1899, Bayer registered ASA as Aspirin® (Afor acetyl and Spiraea, another
plant that contains salicylic acid) as atrademark under
. Fig. 3.1 Salicylic acid 3.2 is the oxidation and cleavage product
of salicin3.1, which is isolated from willow bark. Acetylsalicylic acid
(ASA)3.3 is not simply aprodrug of salicylic acid, but rather adrug
with its own mode of action
the number 36,433. From then on, it was sold as 1 g of
powder in envelopes, and shortly thereafter as tablets.
Detractors alleged that it was only developed in tablet
form so that Bayer could emboss their famous Bayer
cross onto the tablets. Aspirin quickly gained aleading
place in drug therapy. One-hundred years after its market
introduction, 40,000 tonnes of ASA are produced and
pressed into tablets every year, worldwide. At the end
of 1994, the Bayer plant in Bitterfeld produced 400,000
Aspirin® tablets per hour, 3.5billion per year. The importance that the trademark Aspirin had for Bayer became
clear in 1994 when the company paid US$ 1billion to
take over the self-medication business from Sterling-Winthrop, which included the trademark rights for Aspirin,
which had been lost in 1918.
The Spanish philosopher José Ortega yGasset called
the previous century the “Age of Aspirin.” In his book
The Rising of the Masses, he wrote:
“The ordinary person lives today more easily, comfort-
»
ably and safely than the most powerful of the past. Why
should he care that he is not richer than others when the
world is [richer] and roads, trains, hotels, telegraphs, per-
sonal safety, and Aspirin
®
are at his disposal.”
Jaroslaw Hasek, Kurt Tucholsky, Giovanni Guareschi,
Graham Greene, John Steinbeck, Agatha Christie, Truman Capote, Hans Helmut Kirst, and Edgar Wallace
also wrote about Aspirin. The singer Enrico Caruso
treated his headaches with only “German Aspirin,” out
of principle. Even Franz Kafka and Thomas Mann raved
about its outstanding effects in their letters. In 1986 on
an ofcial visit to Germany, Queen ElizabethII said that:
“German successes span the entire breadth of human life.
»
From philosophy, music and literature, to the discovery
of X-rays and the mass production of Aspirin
®
.”
The compliment was wonderful, but one must also consider that all of these scientic discoveries are slightly
more than 100 years old! ASA was considered to be
. • Aspirin: ANever-Ending Story
aprodrug of salicylic acid and adrug of unknown mode
of action until John Robert Vane (Nobel Prize 1982)
and SergioH. Ferreira discovered in 1971 that salicylic
acid and other nonsteroidal anti-inammatory drugs
inhibit prostaglandin G/H synthase (cyclooxygenase,
COX, Sect.27.9). COX, aubiquitously present, membrane-bound enzyme transforms arachidonic acid3.4
over acyclic endoperoxide into PGH2 3.5, which in
turn is transformed into prostacyclin3.6, thromboxane
A23.7, and other prostaglandins. Large quantities of
prostaglandins are produced in inamed tissue; thus,
inhibition of cyclooxygenase mitigates the cause of the
process itself (. Fig.3.2).
ASA is in fact ametabolic precursor of salicylic acid.
In contrast to other anti-inammatory drugs, including
salicylic acid, however, it has an astonishing mode of
action (Sect.27.9). It has been known for some time
that ASA selectively acetylates the hydroxyl group of
the amino acid serine 530 of cyclooxygenase. In 1995,
the three-dimensional complex structure of abromine
analogue was elucidated for the rst time (. Fig.27.41).
This emphasizes that ASA, analogously to other COX
inhibitors, docks near the arachidonic acid binding site.
Therefore, despite its relatively weak binding, ASA is in
an outstanding position to acetylate this serine. Serine
530 is not involved in the catalytic mechanism, but the
additional volume of the acetyl group impedes arachidonic acid’s entrance to the binding site and therefore
the synthesis of the prostaglandin precursors. ACOX
mutant that carries an alanine instead of aserine at position 530 is enzymatically fully active and is inhibited by
every other anti-inammatory compound. However, as
expected, ASA only weakly inhibits this mutant.
Stimulation for the continued research on nonsteroidal anti-inammatory drugs was generated by the discovery in 1991 of asecond cyclooxygenase, COX-2. All anti-inammatory drugs until then were unselective, or they
exerted their effect overwhelmingly over COX-1 and only
slightly over COX-2. The most important side effect of
ASA and other anti-inammatory drugs is the gastrointestinal damage that can occur at high doses. This results
from the inhibition of the COX-1-dependent synthesis of
prostacyclin3.6, which protects the gastric mucosa. In
contrast to the ubiquitously occurring COX-1, COX-2 is
responsible for the rapid synthesis of prostaglandins in
inamed tissue. It has been possible to bring many drugs
to the market that are more than 1000-fold more selective
for COX-2 than COX-1 (Sect.27.9).
But do not worry, Aspirin® will live forever. Its success is growing in another market. Even at low doses
ASA inhibits the synthesis of thromboxane A23.7, which
initiates the coagulation of platelets (thrombocytes). Because of the irreversible inhibition of cyclooxygenase by
ASA and the inability of platelets, which lack anucleus,
to resynthesize their enzymes, even asingle contact with
the substance is enough to suppress synthesis for about
aweek, the lifetime of athrombocyte. In tissues other
than thrombocytes, the enzyme is continuously resynthesized. Therefore, the physiological adversary to thromboxane, the aggregation-inhibiting prostacyclin that is
produced in the walls of the vasculature, can be replenished (. Fig.3.2).
In terms of the condition of increased clotting tendency, ASA thus shifts the biosynthesis from the “bad”
thromboxane to the “good” prostacyclin. This effect
suggests atherapeutic application of ASA in cases of
increased tendency to clot, e.g., before and after myocardial infarction and stroke. Understanding the mechanism
of the antithrombotic effect, it has been suggested that
the doses used for therapy should be reduced by afactor
of10. This simultaneously reduces the risk of gastric and
intestinal bleeding as possible side effects. These considerations led to the recommendation made in the early
2000s, which has in the meantime become highly con-
. Fig. 3.2 Arachidonic acid3.4 undergoes an
oxidative cyclization and aperoxidase reaction in
the prostaglandin biosynthesis to give the primary
product PGH23.5. Finally, prostacyclin synthase
transforms PGH2 into prostacyclin3.6, which
protects the gastric mucosa, dilates blood vessels,
and inhibits platelet (thrombocyte) aggregation. The
platelet thromboxane synthase transforms PGH2
into thromboxane A2, which promotes aggregation.
ASA irreversibly inhibits cyclooxygenase. By using
low ASA doses, thromboxane A2 synthesis in the
platelets is more strongly inhibited than the production of prostacyclin in the vascular walls
Chapter • Classical Drug Research
3
troversial, to take ASA as apreventive treatment during
long-distance ights. Lack of mobility, cramped seating,
coupled with dry air and reduced pressure in the cabin,
leads to dehydration. This causes the blood to “thicken”
and results in changes in its ow velocity. This “economy
class syndrome” could lead to so-called “jet legs” and
could increase the risk of thromboembolism and venous
thrombosis. ASA should actually only have apreventive
effect on arterial thromboses; therefore, this therapy recommendation seems rather controversial. Nevertheless,
studies keep coming up that try to establish abenet in
venous thrombosis. A comprehensive ASPREE study
involving 19,114 healthy seniors without cardiovascular
risk factors were randomized to receive either in the rst
half 100 mg ASA daily or in the second half aplacebo.
The study found no benet for primary prevention. This
makes the success of such prevention highly questionable. By contrast, the use of ASA before surgical interventions is not recommended. Surgeons do not want
their patients to have an increased bleeding tendency due
to reduced clotting ability during surgery.
But other observations do give ASA the potential of
a“preventive drug.” A 6-year observation of 600,000
volunteers is worth an entry in the Guinness Book of
Records. According to their evaluation, ASA appears
to reduce the risk of fatal colon cancer by 40%. However, it must be taken into account in such studies that
because of possible stomach and intestinal bleeding as
side effects of ASA, colonoscopy was probably carried
out more intensively in the treated group than in the untreated reference group. It is quite conceivable that colon
cancer was, thus, detected more frequently at an early
stage that could still be subjected to surgical treatment.
The mode of action of the tumor-protective effect of
ASA has still not really been claried. Both apoptotic
effects and the inuence of ASA on the metastasis of
tumors have been described. The risk reduction of tumors in different tissues when taking ASA appears to
be different. In the meantime, studies have even become
known which, for example, relate the cancer-preventive
prole of ASA to the methylation status of promoters
of certain breast cancer genes. This should be seen as an
indication that even the epigenetic status (Sect.12.14) of
individual patients can be decisive for the effect.
Achewable aspirin tablet has been available since
1992. Here ASA is buffered with calcium carbonate, absorption is faster, and side effects are reduced. But far
be it from anyone who thinks this is as far as it goes. In
2014, Bayer launched anew formulation with sodium
carbonate and highly dispersive silicon dioxide as excipients. In the acidic environment of the stomach, the active ingredient quickly dissolves into very small particles.
This so-called MicroActive technology allows even faster
absorption with accelerated onset of action. ASA has
had an unbelievable career, particularly if one considers
that it would never have had achance to be approved
under modern criteria. Its short plasma half-life, the irreversible protein inhibition, and the high dosage would
have met today’s exclusion criteria. Adenitive endpoint
in this hypothetical development using the contemporary
criteria would be the observation of teratogenicity in rats.
Apathological result in toxicity studies with this animal
model would denitely lead to discontinuation, because
who would dare to wager that ateratogenic effect occurs
in rodents, but not in humans. Aspirin®—really anever-ending story!
3.2 Malaria: Success and Failure
The treatment of malaria begins with the discovery of
cinchona, around which there are numerous legends.
The nicest and most frequently cited version is that of
the fever-stricken Countess Cinchon, the wife of the
Spanish viceroy in Lima, Peru, who was healed by the
physician Juan de Vega in 1638. On the advice of the
town magistrate of Loja, Quinquina the “bark of the
barks” (therefore, the confusing name “cinchona bark”)
was brought in from 800 km away. The Countess was
allegedly healed and from then on distributed the powder
herself. In the older works, the cinchona bark was also
called “Countess powder” or “Jesuit powder.” Perhaps
it was also true that the Indians, who were forced into
compulsory service in the silver mines by their Christian
conquerors, chewed the bark to ght off shivering in the
cold. The clever Jesuits took note of these observations
and thought that chewing the bark would also help with
the shivering that comes from amalarial fever episode.
Cinchona then came back to Europe with the Jesuits.
Malaria, the remittent fever, is awidespread tropical and subtropical disease. Because it is transmitted by
the anopheles mosquito, it occurs particularly in wetlands. Even the city Buenos Aires (Span. “good airs”)
was badly hit by malaria (Ital. mala aria =“bad airs”).
Alexander the Great, the Gothic King Alarich, and the
German Emperors OttoII and HeinrichIV died of it.
Even Albrecht Dürer (1471–1528) apparently suffered
from malaria. He sent his private physician adrawing
of himself in which he was wearing only aloincloth. His
right hand is over his spleen with the additional text that
do der gelb Fleck ist vnd mit dem Finger drawff dewt, do ist
mir we (there where the yellow spot is and where the n-
ger points, is where it hurts). In Europe malaria was still
widespread until the middle of the twentieth century. In
northern Germany, the last epidemics were in the years
1896, 1918, and 1926.
The miasma, emissions from the ground, swamps,
and corpses, were long seen as the source of malaria and
other epidemics. The Roman author Marcus Terentius
Varrus (116–27 BCE) suspected back then that small invisible organisms might be responsible. Towards the end
of the nineteenth century, the anopheles mosquito was
. • Malaria: Success and Failure
. Fig. 3.3 Simple synthetic analogues with antimalarial effects were
derived from quinine3.8. Plasmoquine3.9 still contains the methoxyquinoline ring of quinine, but it is in adifferent position. The later-developed analogues mepacrine 3.10 and chloroquine 3.11 show strong
identied as the vector, and aplasmodium was recognized as the cause of malaria.
Around 1930, there were about 700 million people
infected, and in 2003 the number was estimated to be
300–500 million. Up to 1.2million people die every year,
mostly children under the age of5, and many others suffer permanent injury. Psychiatric changes also result. The
term “spleen” for eccentricity originally came from the
enlarged spleen that malaria causes.
The active substance in the cinchona bark, the alkaloid quinine3.8 (. Fig.3.3), was isolated in 1820. Aside
from the positive therapeutic effects, it also had considerable side effects. Nonetheless, up until afew years ago
it was the most important antimalarial, particularly for
the parenteral treatment of severe malaria. The rst synthetic alternative, plasmoquine3.9, became available in
1927, but it is seldom used due to its side effects. The
later-developed, more potent analogues 3.10–3.12 show
aclear structural relationship to the lead structure quinine (. Fig.3.3). It was only through the protection
from malaria that the exploitation of the colonies was
possible.
The World Health Organization (WHO) initiated
aglobal malaria eradication program in 1955 mainly
through the use of the insecticide dichlorodiphenyltrichloroethane 3.16 (DDT, . Fig.3.4). The success was
overwhelming; the number of cases and fatalities was reduced to practically zero (. Table3.1). In 1953, it was estimated that ve million lives had been saved since 1942.
In India alone, the number of cases went from 75million
to 750,000, and the number of annual fatalities was reduced to 1500. DDT has saved more lives than all anti-
similarity to quinine. The newer derivatives meoquine 3.12 and amodiaquine 3.13 are also structurally closely related to quinine. With AQ13 3.14 and ferroquine 3.15, aferrocene sandwich complex, two new
substances from the chloroquine family are available
malarial drugs put together! The acute toxicity of DDT
is actually not aproblem for mammals and humans.
Unfortunately, it turned out that DDT decomposes extremely slowly in the environment, and it enriches as it
moves its way up the food chain, especially in birds and
sh. It also accumulates in human fat and in breast milk.
The chronic toxicity comes from long-term retention of
one year or more, which is aserious problem.
The moving book Silent Spring by Rachel Carson was
published in 1962. Despite warnings from experts, DDT
spraying for mosquitoes was stopped in Sri Lanka in
1963, and the number of malaria cases raced to 2.4million by 1968/1969. By then it was too late to use DDT
again because the mosquitoes had become resistant, and
this was certainly also partially due to the residual DDT
that remained in the environment in the intervening
years.
Further investigations showed that aDDT metabolite, dichlorodiphenyldichloroethylene 3.17 (DDE,
. Fig. 3.4) has surprisingly strong antiandrogenous
effects, that is, it blocks the effects of male hormones.
Therefore, DDE is responsible for the DDT-dependent
reproductive and developmental disorders that are seen
in some species, perhaps also in humans. It is remarkable that the effect of this metabolite was only discovered
50years after DDT was introduced.
Not only the mosquitoes became resistant to DDT,
the parasite also became resistant to the drugs. For this
reason, the history of the chemotherapeutic developments for malaria has been arollercoaster ride of new
promising compounds, and the more or less quick development and distribution of resistant parasites.
Chapter • Classical Drug Research
3
Chloroquine 3.11 was prepared in 1934 in the Bayer
laboratories, but was judged to be “too toxic.” It was “rediscovered” by the Americans and deployed as amalaria
therapeutic par excellence. Efcacious, well tolerated,
and above all else inexpensive to produce, it, along with
the above-described mosquito extermination with DDT
and landscaping measures, brought us within reach of
avictory over malaria. It is regarded as an inhibitor of
hemoglobin utilization. The malaria pathogen degrades
hemoglobin in infected red blood cells to obtain proteins
for its metabolism. Chloroquine inhibits the crystallization of hemozoin, adegradation product of hemoglobin.
If hemozoin can no longer be crystallized, the parasite
dies. However, as early as in the 1960s, in various places
in Southeast Asia, Oceania and South America, independently and almost simultaneously resistant parasites
emerged. They possessed amutated transport protein in
the membrane of their gastriole that recognizes chloroquine as asubstrate. By using this protein, they were able
to expel chloroquine from its target. In the meantime, resistant parasites have spread throughout almost the entire
geographic range of malaria. Chloroquine lost its once
phenomenal status for the treatment of malaria tropica.
Since then, amalaria therapeutic with similar qualities as chloroquine has been sought by researchers, until
now, however, without success. The structurally related
amodiaquine 3.13 (. Fig.3.3) is in fact effective against
weakly chloroquine-resistant strains, but it is largely
ineffective against highly resistant strains (especially in
Southeast Asia). Moreover, upon long-term use as aprophylaxis, it carries the risk of irreversible liver damage or
life-threatening agranulocytosis. Research has produced
two new substances from the chloroquine family, AQ-13
3.14 and ferroquine 3.15 (. Fig.3.3), an exotic-looking
iron-sandwich complex.
In the short term, it appeared that the antifolate
combination of sulfadoxine/pyrimethamine 3.18/3.19
(Fansidar®) could replace chloroquine (. Fig.3.5), but
the rst resistance occurred much faster than with chloroquine. Starting from the point of origin in Southeast
Asia, the resistance has spread throughout the world.
The wars of the last century have also promoted the
search for new antimalarial drugs. Tremendous effort
. Fig. 3.4 The insecticide p,p′-dichlorodiphenyltrichloroethane 3.16
(DDT) saved more human life than all of antimalarials put together.
The latest investigations show though that the antiandrogenic effects
of the main metabolite p,p′-dichlorodiphenyldichloroethylene 3.17
(DDE) is possibly the main culprit responsible for reproductive disorders found in animals, including perhaps humans
. Table 3.1 Number of malaria cases in different countries
before and after the introduction of DDT 3.16 (. Fig.3.5).
The numbers in parentheses are the years. (From T.H. Jukes
(1974) Naturwiss.61, 6–16)
Country Cases of malaria (year)
Before DDT After DDT
Italy 411,602 (1946) 37 (1969)
Spain 19,644 (1950) 28 (1969)
Yugoslavia 169,545 (1937) 15 (1969)
Bulgaria 144,631 (1946) 10 (1969)
Romania 338,198 (1948) 4 (1969)
Turkey 1,188,969 (1950) 2173 (1969)
India ~ 75million per year ~ 750,000 (1969)
Sri Lanka 2.8million (1946) 110 (1961)
31 (1962)
17 (1963)
2.5million
(1968/1969)
Taiwan > 1million (1945) 9 (1969)
Venezuela 817,115 (1943) 800 (1958)
Mauritius 46,395 (1948) 17 (1969)
a
Imported cases
b
After DDT spraying was discontinued in 1963
a
a
a
a
b
was made at the Walter Reed Army Institute of Research in the USA. Over the course of 40 years, and
particularly during World WarII and the Vietnam War,
more than 250,000 substances were tested for an antimalarial effect. Considering the exerted effort, success was
modest: the two aryl amino alcohols halofantrine 3.20
and meoquine 3.12, and the 8-aminoquinoline tafenoquine 3.21, which was approved in the US in 2018. After
its introduction, halofantrine was withdrawn from the
market because it caused lethal arrhythmias (Sect.30.3).
In Southeast Asia, the resistance to meoquine developed so quickly that it can only be used in combination
with artesunate 3.22. Because meoquine has been used
sparingly due to its price, most of the parasite strains
are still sensitive to it. For this reason, today meoquine
is one of the most important malaria prophylactics for
Western tourists. Artesunate is apartial-synthetic derivative of dihydroartemisinin 3.24, which is produced
by reducing artemisinin. It is isolated from annual mugwort (Artemisia annua). In the early 1970s, the Chinese
scientist Tu Youyou extracted the compound from the
plant and tested its effectiveness against malaria. In
2015, Youyou was awarded the Nobel Prize for Medicine
for this achievement. The mechanism of action of arte-
. • Malaria: Success and Failure
. Fig. 3.5 Recent research on antimalarial drugs has described nu-
merous products, often used in combination. Fansidar, acombination
of sulfadoxine 3.18 and pyrimethamine 3.19, was initially considered
the drug of choice. However, the development of resistance has rendered even this promising drug useless. At present, hopes are pinned
on the artemisinin derivatives 3.22 and 3.24, and another member of
misinins is still not fully understood. What is unusual is
their endoperoxide structure, which is essential for their
action. Cleavage of the endoperoxide bridge generates
reactive oxygen species (ROS) that can induce apoptosis. Oxidative stress increases in infected red blood cells.
As aresult, the level of unfolded proteins increases and
hemoglobin degradation is impaired. Activation of
caspase-like enzymes and DNA fragmentation indicate
the initiation of apoptotic cell death. Thus, artemisinins
inhibit the nutritional process of the parasites.
The artemisinins are currently the most effective
antimalarial drugs for rapid control of the parasites.
Unfortunately, resistance to these compounds has begun to emerge. Today, artemisinin-based combination
therapy is the WHO recommendation. Combinations
are made with whatever is available, including sub-
this family, artefenomel 3.32, is available. Fosmidomycin 3.31 inhibits the mevalonate-independent biosynthetic pathway for isoprenoid
synthesis, and DSM265 3.33 inhibits dihydroorotate dehydrogenase,
an enzyme essential for pyrimidine neosynthesis in malaria pathogens.
Cipargamine 3.34 blocks aparasite-specic membrane pump, and the
mechanism of action of KAF156 3.35 remains to be elucidated
stances to which massive resistance has already been
observed. One combination is made with the arylaminoalcohol lumefantrine 3.23, which was developed in
China and is still very effective. Dihydroartemisinin/
piperaquine (Eurartesim®) 3.24/3.25 and artesunate/
pyronaridine (Pyramax®) 3.22/3.26 have also been approved as combination preparations (. Fig.3.5). Both
artemisinin combination partners were developed in
China in the 1960s and 1980s, respectively. Although
pyronaridine has an aza-acridine rather than aquinoline parent scaffold, they belong to the same class of
drugs as chloroquine. Resistance to these two drugs is
already widespread in Southeast Asia. The combination
of dapsone/chloroproguanil (Lap-Dap®) 3.27/3.28 belongs to along-established class of antifolates. Again,
most Southeast Asian strains are already resistant. It
Chapter • Classical Drug Research
3
was withdrawn from the market in 2008 due to toxicity
concerns. Real novelties in the mechanism of action are
rare. In 1997, the very expensive combination atovaquone/proguanil 3.30/3.29 (Malarone®) was introduced,
which synergistically inhibits the mitochondrial respiratory chain. Apromising candidate was the antibiotic
fosmidomycin 3.31 which inhibits a parasite-specic,
mevalonate-independent pathway for isoprenoid synthesis. Increased efforts are needed to nd new compounds.
Artefenomel 3.32 is anew analogue of the artemisinin
family in clinical development. It is characterized by
asignicantly longer half-life and has the potential to
achieve therapeutic success with asingle dose. Inhibitors
of dihydroorotate dehydrogenase have also been sought
for some time. The enzyme is essential for the malaria
pathogen in the pyrimidine resynthesis of DNA building
blocks. With DSM265 3.33, ahopeful candidate may be
in clinical trials. Cipargamine 3.34, aspiroindolone, can
inhibit aparasite’s own membrane pump, thereby per
manently disrupting the osmotic balance of the pathogens. Furthermore, KAF156 3.35, anew imidazole piperazine, is in clinical trials for which the mechanism of
action still needs to be claried. Thus, several substances
are currently being developed as promising candidates
with alternative action proles. Only this way can we be
prepared for the time when resistance to artemisinins
increasingly manifests itself.
As an alternative to drug therapy, vaccine developments have been advanced for many years. Although
plasmodia are single-cell organisms, they prove to be
extremely adaptable, also due to the change of host.
Equipped with more than 5400 genes, they repeatedly
manage to change their surface structures so strongly
through variation in protein expression that our immune
system must constantly re-adjust to seemingly changed
parasites. Nevertheless, the rst eld studies with the
vaccine Mosquirix®, which contains an articially
produced fusion protein of certain surface areas of the
parasite as an antigen, started in 2019. In humans, this
is intended to trigger antibody production (Sect.32.3)
in order to eliminate the parasite before it spreads in
the red blood cells in the event of disease. Afurther development of Mosquirix® with optimized antigen and
better adjuvant is the R21/Matrix-M malaria vaccine.
It provides about 80% protection. Approval in 2023
for children aged 5 to 36months in Ghana is based on
aPhaseIII study involving 4800 children. Work is also
underway on living vaccines that activate CD8+ Tcells to
eliminate infected cells in the human body (Sect.31.7).
In addition, anumber of mRNA-based malaria vaccine
candidates are currently under development at BioNTech. It remains to be seen whether this will achieve the
grand goal of one day eradicating malaria. However, it
should not be forgotten that exposure prophylaxis with
mosquito nets or repellents still plays an important role
in the control of malaria.
-
3.3 Morphine Analogues: AMolecule Cut
to Pieces
Research on opiates has taught us how complex natural
products can be systematically simplied, and structurally
abbreviated analogues can be prepared that have the identical effect, but sometimes with even better specicity. It has
also shown that there is sometimes no obvious solution for
aspecic problem. Separation of the analgesic and addictive qualities could not, or only inadequately be achieved.
The narcotic, analgesic, and euphoric effects of opium,
which is isolated from poppies, have been known for at
least 5000 years. Opium was used for operations, but is
also a commonly abused drug. The importance of its
abuse in the cultural history of humanity is illustrated,
among other places, in the “Opium Wars” of the nineteenth century. In 1840, the Chinese wanted to stop the
English from importing opium and burned 20,000 cases of
it; this led to a2-year-long war between the two countries.
In 1804/1805, the pharmacy assistant Friedrich
Wilhelm Adam Sertürner of the Hof-Apotheke in Paderborn, Germany, isolated the compound with the
sleep-inducing principle. He named it morpheum (later
morphine) after Morpheus, the Greek god of dreams and
son of Hypnos. Morphine addiction took on awhole new
dimension after 1853 with the invention of the hypodermic needle and syringe by CharlesG. Pravaz and Alexander Wood. As aresult, morphine and heroin addiction
spread widely, and in the history of humanity it is one of
many examples of the misuse of abenecial discovery.
Morphine 3.36 (. Fig.3.6) is one of the few examples
of anatural product that is still used today in its original
form. It belongs to the most potent known analgesics. If it
is administered according to the correct dose and schedule,
the danger of addiction is low. The addictive potential is
often overestimated by physicians such that patients with
severe pain are often inadequately treated with opiates.
Morphine is also aprime example of the success of systematic structural variation in the direction of more-easily
manufactured, simpler analogues as well as more selective
activity. The rst modied products were simple derivatives
such as the methyl ether codeine 3.37, which is also found
in poppies. Codeine is weaker than morphine, but it is bioavailable after oral administration. It has apronounced
antitussive effect and alow addictive potential. Unfortunately, the opposite is true for the potent, fast-acting diacetyl derivative heroin 3.38. It has enormous addictive potential. Today it seems ironic that at the end of the nineteenth
century Heinrich Dreser, asenior pharmacologist at Bayer,
wanted to discontinue the development of Aspirin® because of asuspected cardiotoxicity in favor of developing
heroin as awell-tolerated and potent cough medicine (sic!),
at least until he realized the mistake. Arthur Eichengrün at
Bayer tested ASA on himself without any side effects. He
was nally able to convince Carl Duisberg to continue with
ASA, which ultimately led to the drug's approval for ther-
. • Morphine Analogues: AMolecule Cut to Pieces
apy. Eichengrün must therefore be regarded as another father of ASA. Of all the morphine derivatives, codeine and
heroin are the most widespread: codeine is in numerous
combination preparations, and heroin is in the drug scene.
Some n-alkyl derivatives of morphine and close analogues,
for instance, naloxone 3.39, are opiate antagonists, that is,
they inhibit the effect of morphine (. Fig.3.6).
The structural elucidation of morphine took more
than 120 years, and its total synthesis, and ultimate
structural proof, was completed in 1952 by Marshall
Gates and Gilg Tschudi. Morphine contains ve rings:
an aromatic benzene ring, two unsaturated six-membered rings, the nitrogen-containing piperidine ring, and
an oxygen-containing ve-membered ring. Systematic
structural modications had the goal of simplifying the
structure, for example, by opening one or more rings, or
removing them altogether.
In 1939, the potent analogue pethidine 3.40 (. Fig.3.7)
was the rst fully synthetic analgesic, though it was originally based on the spasmolytic atropine 3.41. Despite this,
it is recognized to be amorphine analogue. In levomethadone 3.42, the piperidine ring of pethidine is opened, an
oxygen atom from the ester group is removed, and another
aromatic ring is added. There are thousands of other analogues, some of which have been introduced to therapy.
Aside from the deconstruction of morphine, the construction of additional rings has surprisingly led to more potent
analogues, for example, etorphine 3.43 (. Fig.3.7).
For along time, it was acomplete mystery why our bodies would have extra receptors for the contents of poppy
plants, so-called opiate receptors. The solution came with
the discovery of the endogenous morphine-like peptides
Met- and Leu-enkephalin (Sect.10.2), which are the natural ligands for these receptors. The discovery stimulated an
intensive search for orally active peptides or peptidomimetics devoid of addictive potential. The result of the work
was more than sobering. Although orally active analogues
were found, their addictive potential was identical to that
of morphine and most morphine-derived analogues.
Afew synthetic analogues have, in addition to agonistic activity, a weak antagonistic effect as well. The
potential for these substances to be abused by addicts is
less than with the classical morphine analogues. Combination preparations of agonists and antagonists are also
available. With appropriate use, the analgesic effect of
the agonist dominates because it is present in excess. If
the medicine is injected intravenously, the more-strongly
binding antagonist displaces the agonist, and the desired
euphoric effect never sets in.
The work with regard to improved selectivity was
also successful. Today cough medicines and antidiarrhea
medicines, for example, loperamide 3.44 (. Fig.3.8), are
available that have no central morphine-like effects. This
substance is able to pass through the blood–brain barrier but is immediately expelled by an active transporter.
Upon inhibition of these transporters, for instance, when
. Fig. 3.6 Morphine 3.36 and codeine 3.37 served as lead structures
for heroin 3.38, which has better CNS bioavailability, and naloxone
3.39, amorphine antagonist
. Fig. 3.7 The architecture of morphine was dissected in many ways.
The strongly potent pethidine 3.40, the rst fully synthetic opiate analgesic, was discovered in the 1930s in asearch for anticonvulsives by varying
the structure of atropine 3.41. It is recognizable, however, that pethidine
retains the benzene ring of morphine as well as its piperidine ring. Levomethadone 3.42 is derived from pethidine. The addition of another ring
led to substances with apotency that surpasses morphine by orders of
magnitude. Etorphine 3.43 is 2000- to 10,000-times more potent than
morphine in animals. Since 1963, it is used in African wildlife preserves
to immobilize large animals such as elephants and rhinoceroses
coupled with quinidine, loperamide also has classical
opiate effects. Its structure unites elements of pethidine
3.40 and levomethadone 3.42.
In this section, only a few representatives of the
many thousand structural modications of morphine
can be discussed. The approach of Paul Janssen should
not remain unmentioned though. He started with pethidine 3.40 with the goal of preparing astrong analgesic,
but instead experienced unexpected success in another
area. The result was the neuroleptic haloperidol 3.45
(. Fig.3.8), adrug for the treatment of schizophrenia,
the mode of action of which is mediated by an antagonistic effect at the dopamine D2 receptor (Sect.29.1).
3
Chapter • Classical Drug Research
. Fig. 3.8 Structural derivatives of morphine and its ana-
logues have led to selective antidiarrhea agents, loperamide
3.44, for instance, as well as neuroleptics such as haloperidol
3.45
3.4 Cocaine: Drug and Valuable Lead
Structure
No other substance sparkles in so many ways as cocaine. It is at the pinnacle of all illegal drugs. In 2017
alone, investigative authorities seized 552 tonnes of cocaine worldwide. The smuggling methods are becoming
rougher and rougher, for example, people are sent on the
journey between continents as living transporters with
swallowed cocaine-lled condoms. The amount that ultimately ends up for consumption in Europe is estimated at
around 150 tonnes per year. Cocaine was also the chemical starting material for awide palette of valuable local
anesthetics and antiarrhythmics. We can thank the lead
structure cocaine for local anesthesia, pain-free dentistry,
and nerve block anesthesia for smaller surgical procedures. The translation of the quite positive central effects
of cocaine onto analogues devoid of addictive potential
is still in progress. The example of morphine leads one
to fear that this goal might not be possible.
Coca leaves and cocaine 3.46 (. Fig.3.9) belong to
the oldest known drugs. Chewing dried coca leaves has
along tradition in Peru and Bolivia. In 1744, Garcilaso
de la Vega wrote that coca “satises hunger, gives new en-
ergy to the tired and exhausted, and lets the unhappy forget
their troubles.” The Scottish author Robert Louis Steven-
son (Treasure Island) wrote in his novella The Strange
Case of Dr. Jekyll and Mr. Hyde about apersonality split
that adoctor undergoes under the inuence of drugs. He
wrote the rst draft of this novella in only three days and
nights, while under the inuence of cocaine.
In 1863 the American chemist Angelo Mariani (1838–
1914) patented amixture of coca extract and wine as Vin
Mariani. It made him arich man. In 1886, the pharmacist
JohnS. Pemberton developed acoca-containing stimulant and headache remedy that he named Coca-Cola. He
sold the rights in 1891 to acolleague, A.G.Chandler,
who founded the Coca-Cola Company one year later. Up
until 1906, Coca-Cola indeed contained asmall amount
of cocaine, but today it only contains the harmless stimulant caffeine. Back at the turn of the twentieth century,
cocaine was already fashionable, particularly in artistic
circles. The Viennese psychiatrist Sigmund Freud (1856–
1939) experimented with cocaine intensively and rather
uncritically. He considered it to be awonder drug, took
it himself regularly, and recommended it generously for
use in therapy, for the treatment of stomach aches, and
for adepressed mood. Later, after massive criticism from
his colleagues he turned away from it. In the Andes of
South America, one of the important cultivation areas
of the coca bush, coca sweets and chewing gum are sold
in supermarkets alongside coca tea. They are used by
the general population as atreatment for high altitude
sickness.
Cocaine causes the release of dopamine from its
transporter (see Sect. 22.7). Usually it is sniffed, occasionally it is intravenously injected, or it is mixed in
drinks or taken orally. Snifng delivers it quickly to the
brain where it displaces dopamine from the binding site
of the transporter and this causes increased dopamine release into the synaptic gap. The free base, which is made
by mixing it with sodium bicarbonate (crack) is absorbed
very quickly through the lungs by smoking it, and causes
euphoria that is even distinctly stronger than when the
salt (coke, powder, snow) is sniffed. Because cocaine does
not bind for long, the transporter is quickly reloaded
with dopamine. The same effect can be induced again
after alittle while. Other cocaine analogues that bind for
longer do not allow the effect to be repeated for hours.
Psychological dependence occurs very quickly, even after
the rst use in the case of crack cocaine. Physical withdrawal symptoms, as seen with heroin addicts, usually
do not occur.
The credit for discovering the local anesthetic effect
of cocaine does not go to Freud but rather afriend of his,
the ophthalmologist Carl Koller (1857–1944). Freud had
planned to investigate this effect but in 1884 he wanted to
rst visit afriend of his, Martha Bernays, in New York.
Koller picked up on Freud’s suggestion and carried out
the decisive experiment on the eye in his absence. The
synthetic benzoic acid esters and anilides that were initially used as local anesthetics were not derived from cocaine 3.46, but rather from p-aminobenzoic acid esters;
benzocaine 3.47 was already used in therapy in 1902.
Astructural relationship to cocaine is, however, easily
seen in modern local anesthetics such as lidocaine 3.48
and mepivacaine 3.49 (. Fig.3.9 and Sect.30.4).
. • H Antagonists: Ulcer Therapy Without Surgery
. Fig. 3.9 The local anesthetic effect of cocaine 3.46 was recognized
early on. The independently found lead structure benzocaine 3.47 and
the basic moiety of cocaine were models for synthetic local anesthetics. The structural relationship is clearly recognizable in lidocaine 3.48,
which also acts as an antiarrhythmic, and in mepivacaine3.49
3.5 H
Antagonists: Ulcer Therapy
2
Without Surgery
The history of the treatment of gastroduodenal ulcers
is long and educational. Basic research claried the important mechanisms without providing anew drug. The
development of the therapy occurred in several phases.
Again and again, new wasn’t necessarily better. In the
beginning, the treatment consisted of antacids, and later
anticholinergics. In severe cases, only surgery helped. The
H2 antagonists made the breakthrough to purely pharmaceutical treatment. Now we are experiencing the victory
lap of the proton pump inhibitors, which are used in different combinations with antibiotics. Perhaps in the future this will be augmented or even replaced by avaccine.
Gastric and duodenal ulcers are usually chronic illnesses and are widespread in the general population. Any
damage to the mucosal membrane of the stomach leads
to damage to the underlying cells through proteolytic
enzymes and gastric acid. Acetylcholine 3.50, histamine
3.51, and gastrin, amixture of peptides with 17 (little
gastrin) and 34 (big gastrin) amino acids, stimulate the
production of acid (. Fig.3.10).
For decades the treatment of gastroduodenal ulcers
was based on reducing the amount of acid, for instance,
with sodium bicarbonate, calcium carbonate, basic magnesium salts, and aluminum oxide hydrate. Advanced
ulcers had to be treated surgically. Anticholinergics, antagonists of the acetylcholine receptor should, in principle, have been suitable for ulcer treatment; however, unspecic antagonists are out of the question because of
their severe side effects. It was not until pirenzepine 3.52
(. Fig.3.10), aselective so-called M1 antagonist, was
developed that this class could be used in therapy. Here
. Fig. 3.10 Acetylcholine 3.50 and histamine 3.51 stimulate acid
production in the stomach. The acetylcholine receptor antagonist
pirenzepine 3.52 was the rst drug specically for ulcer therapy. Classical H1 antihistamines such as diphenhydramine 3.53 cannot antagonize histamine in the stomach
the undesirable side effects of unspecic anticholinergics
are only apparent at relative high doses.
The role of histamine in acid secretion was initially
called into question because the classical antihistamines,
later dened as H1 antihistamines, did not reduce acid secretion. These substances, for instance, diphenhydramine
3.53 (. Fig.3.10), antagonize histamine in the intestines,
lungs, and in allergic reactions. Today awide palette of
different histamine antagonists is available for the treatment of allergic rhinitis (hay fever). The most important
side effect, particularly with older substances, is amore
or less pronounced sedation.
Histamine-induced gastric acid secretion, the effect
on the heart, and uterus contractions are not inhibited
by diphenhydramine and other analogues. It was rst
suspected in 1948 that there might be two different his-
tamine receptors, H1 and H2. The H1-type is inhibited by
diphenhydramine, but the H2-type, which is responsible
for the above-mentioned effects is not. Both belong to
the family of G-protein-coupled receptors (Sect.29.1).
In the meantime, two additional members of the family,
the H3 and H4 receptors, have been discovered. In 1964,
JamesW. Black (1924–2010) at Smith Kline & French
in England began to develop three models to test the
inhibition of these other effects of the H2-mediated effect
of histamine. One was an in vivo model measuring gas-
tric perfusion on anesthetized rats, and two were in vitro
models evaluating the histamine-induced stimulation of
aguinea pig heart and arat uterus. James Black later
received not only the Nobel Prize, but was also knighted
by Queen ElizabethII, two rather unusual honors for an
industrial pharmaceutical researcher.
Despite all strategies that were available for the development of receptor antagonists, the search for an H2