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Chapter • Drug Research: Yesterday, Today, and Tomorrow
1
Bibliography and Further Reading
General Literature
R. Schmitz, Geschichte der Pharmazie, Bd.1, GOVI-Verlag, Eschborn
(1998)
C. Friedrich and W.-D. Müller-Jahncke, Von der Frühen Neuzeit bis
zur Gegenwart, Vol. 2, GOVI-Verlag, Eschborn (2005)
W.-D. Müller-Jahnke and C. Friedrich, Arzneimittelgeschichte, Wis-
senschaftliche Verlagsgesellschaft, Stuttgart (2005)
S. H. Barondes, Molecules and Mental Illness, Scientic American Li-
brary, W. H. Freeman and Company, New York (1993)
R. M. Restak, Receptors, Bantam Books, New York (1994)
T. J. Perun and C. L. Propst, Eds., Computer-Aided Drug Design.
Methods and Applications, Marcel Dekker, New York (1989)
C. R. Beddell, Eds., The Design of Drugs to Macromolecular Targets,
John Wiley & Sons, Chichester (1992)
E. C. Herrmann and R. Franke, Eds., Computer Aided Drug Design in
Industrial Research, Ernst Schering Research Foundation Work-
shop 15, Springer-Verlag, Berlin (1995)
K. Müller, Eds., De Novo Design, Persp. Drug Discov. Design, Vol. 3,
Escom, Leiden (1995)
B. Werth, The Billion-Dollar Molecule. One Company’s Quest for the
Perfect Drug, Touchstone, New York (1994)
D. Fischer and J. Breitenbach, Eds., Die Pharmaindustrie, Spektrum
Akademischer Verlag, Heidelberg, Berlin (2003)
A. Giannis, Naturstoffe im Dienst der Medizin - Von der Tragödie zur
Therapie, Springer-Verlag GmbH, (2023)
Special Literature
E. Mutschler, Arzneimittel – Erfolge, Misserfolge, Hoffnungen, Deut-
sche Apoth.-Ztg. 127, 2025–2033 (1987)
D. J. Newman and G. M. Cragg, Natural Products as Sources of New
Drugs over the Last 25 Years, J. Nat. Prod. 70, 461–477 (2007)
C. R. Noe and A. Bader, Facts Are Better Than Dreams, Chem. Britain
29, 126–128 (1993), (formulas of Kekulé and Loschmidt)
C. R. Beddell, P. J. Goodford, F. E. Norrington etal., Compounds
Designed to Fit a Site of Known Structure in Human Hemoglobin,
Br. J. Pharmac., 57, 201–209 (1976)
P. Kramer, Listening to Prozac, Viking, New York (1993)
P. R. Breggin and G. R. Breggin, Talking Back to Prozac, St. Martin’s
Press, New York (1994)
https://data.who.int/dashboards/covid19/cases (Last accessed Nov. 29,
2024)
In the Beginning,
There Was Serendipity
Contents
2.1 Acetanilide Instead of Naphthalene:
ANew, Valuable Antipyretic – 16
2.2 Anesthetics and Sedatives: Pure Accidental Discovery – 16
2.3 Fruitful Synergies: Dyes and Pharmaceuticals – 17
2.4 Fungi Kill Bacteria and Help with Syntheses – 18
2.5 The Discovery of the Hallucinogenic Eect of LSD – 19
2.6 The Synthetic Route Determines the Structure – 19
2.7 Surprising Rearrangements Lead to Medicines – 20
2.8 A Long List of Accidents – 21
2.9 Where Would We Be Without Serendipity? – 21
2.10 Synopsis – 22
Bibliography and Further Reading – 22
© The Author(s), under exclusive license to Springer-Verlag GmbH, DE, part of Springer Nature 2024
G. Klebe, Drug Design, https://doi.org/10.1007/978-3-662-68998-1_2
Chapter • In the Beginning, There Was Serendipity
2
“Alucky accident dropped the medicine into our hands;”
this is how apublication on August14, 1886, from Arnold Cahn and Paul Hepp in the Centralblatt für Klin-
ische Medizin began. The history of drug research is
punctuated by lucky accidents. As ageneral rule, detailed
knowledge of biological systems was absent. Therefore,
it is not surprising that the working hypotheses were
often wrong, and the obtained results differed from expectations. The case of accidental success fell into the
background over time. Today, happenstance as astrategy
has been replaced by the arduous and ambitious goal of
preparing drugs by using astraightforward approach.
The only exception to this is the kind of shotgun-style
testing of large and diverse chemical compound libraries,
including microbial and plant extracts that is done with
the goal of nding new lead structures. In this case, serendipity is desired to nd as large and diverse apalette
of lead structures (Chaps.6, 7, 8, 9).
2.1 Acetanilide Instead of Naphthalene:
ANew, Valuable Antipyretic
Back to Cahn and Hepp. What happened? There are several legends about this lucky accident. The most plausible version is that the antipyretic effect of naphthalene,
acompound widely available from coal tar, was tested.
The substance indeed showed fever-lowering qualities.
The responsible substance however, was not naphthalene
but rather something entirely different: acetanilide2.1
(. Fig.2.1). Further experiments conrmed the efcacy.
Shortly thereafter, the company Kalle & Co. introduced
it to the market with the name “Antifebrin.”
Phenacetin 2.2 (. Fig. 2.1) was subsequently de-
veloped based upon atargeted approach. At the time,
Bayer in Elberfeld had 30 t of p-nitrophenol, a side
product from dye production, on their waste heap. The
then 25-year-old Carl Duisberg, who later became the
chairman of Bayer Farbenfabriken AG and who also
took aleading role in the foundation of I.G. Farbenindustrie in 1924, wanted to use p-nitrophenol for the
preparation of acetanilide as it could easily be reduced
to p-aminophenol. The known toxicity of phenol groups
led to the design of p-ethoxyacetanilide2.2 (phenacetin),
which actually did have the desired qualities and served
as an analgesic for headaches and as an antipyretic for
acentury. Unfortunately its metabolite2.4, which still
contains the ethoxy group, leads to the production of
methemoglobin, an oxidized form of the red blood pigment that is incapable of carrying oxygen. Furthermore,
chronic misuse by, for instance, taking kilogram quantities of phenacetin over alifetime, leads to kidney damage. Paradoxically, the main metabolite of phenacetin,
p-hydroxyacetanilide2.5 (. Fig.2.1, acetaminophen in
American English, or paracetamol in UK English) is actually responsible for the effect, and it is less toxic and
better tolerated. In the USA alone, paracetamol achieved
over US$ 1.3billion in annual sales. This is even more
than for acetylsalicylic acid.
2.2 Anesthetics and Sedatives:
Pure Accidental Discovery
In 1799, Humphry Davy (1778–1829) discovered the
euphoric effect of nitrous oxide (N2O), which was appropriately named “laughing gas.” The dentist Horace
Wells (1815–1848) saw atraveling theater production of
a“snifng party” with N2O in 1844 in which aparticipant suffered from aesh wound, apparently without
pain. To test this effect, Wells had one of his own teeth
extracted, also without pain. He then repeated the procedure on many people, with success. However, one public
demonstration went awry, and this drove him to suicide
four years later. It’s frightening how things keep repeating themselves. Recently, nitrous oxide has been increasingly used as amodern party drug. Its strong euphoric
effect, sometimes combined with drowsiness and even
. Fig. 2.1 By starting with the accidently discovered
acetanilide2.1, Carl Duisberg planned the synthesis of
phenacetin2.2 from nitrophenol2.3. In contrast to the toxic
metabolite2.4, the main metabolite, paracetamol (Amer. acetaminophen)2.5 is well tolerated
. • Fruitful Synergies: Dyes and Pharmaceuticals
hallucinations, is obviously appealing. Unfortunately,
the risks are underestimated as frequent application can
severely damage the nervous system.
The same effect was observed in 1842 by CrawfordW.
Long (1815–1878) with ether, but he did not report it
immediately. After administering ether, he was able to
remove an ulcer from the neck of avolunteer. WilliamT.
Morton (1819–1868) successfully carried out the rst
ether anesthesia in the same hospital as Wells. Starting in
1847, chloroform was used as an anesthetic. Afew years
later, anesthesia became standard for surgical procedures,
areal blessing for the suffering of humanity.
Oskar Liebreich (1839–1908) wanted to develop adepot form of chloroform2.6 in 1868. Because chloral hydrate can be cleaved with base in an aqueous milieu, he
hoped that this could also happen in the body. Chloral
hydrate is in fact asedative, but this is because of its
active metabolite, trichloroethanol2.8 (. Fig.2.2), and
not because it releases chloroform.
In 1885, Oswald Schmiedeberg (1838–1921) tested
urethane 2.9 (ethylcarbamate, . Fig. 2.3) because he
thought that it would release ethanol in the organism.
Urethane itself is the active agent. Its optimization later
led to isoamylcarbamate 2.10 (Hedonal®, 1899). Based
on this, open and cyclic carbamates and ureas were investigated. In 1903, the rst barbiturate sedative, barbital (Veronal®) resulted. In the decades that followed,
awealth of better-tolerated barbiturates with abroader
pharmacokinetic spectrum were introduced.
. Fig. 2.2 The anesthetic chloroform2.6 is formed upon treatment
of chloral hydrate2.7 with base. However, this reaction does not work
in vivo. The active metabolite of2.7 is trichloroethanol2.8
2.3 Fruitful Synergies:
Dyes and Pharmaceuticals
Dyes and pharmaceuticals have stimulated one another.
The rst synthetic dye was the result of afailed drug synthesis. In 1856, August Wilhelm v.Hoffman assigned the
task of synthesizing quinine, an alkaloid used for treating malaria (Sect.3.2), to the then 17-year-old William
Henry Perkins (1838–1907). By starting with only the
molecular formula, it was anticipated that the oxidation
of an allyl-substituted toluidine would deliver the desired
product. However, now that the structural formula is
known, we understand that this could not possibly have
worked! Upon oxidation of aniline that was contaminated with o- and p-toluidine, Perkins isolated adark precipitate. It contained adye, mauveine 2.12 (. Fig.2.4)
that colored silks abrilliant mauve. Other dyes were prepared in rapid succession. The development and later
proliferation of the dye industry in England and Germany in the second half of the nineteenth century can
be traced back to this accidental discovery. Towards the
end of the nineteenth century increasing competition and
adifcult economic situation in the dye market inspired
the reactionary expansion into industrial pharmaceutical
research. In 1896, apharmaceutical research laboratory
was founded in the 33-year-old Bayer Farbenfabrik. At
that time innumerable synthetic dyes were known; therefore, it is not surprising that these substances were tested
for pharmacological effects.
Of all people, wine adulterators played an important
role in the discovery of the rst synthetic laxative. To
stop people from selling Trester wine (so-called Nach-
wein) as anatural wine (Naturwein), in 1900 the dye phe-
nolphthalein was added as an easily detectable indicator.
The Hungarian pharmacologist Zoltán von Vámossy
(1868–1953) investigated the effects of this compound.
Back then, the conventions of the pharmacologists were
. Fig. 2.3 The hypothetical “prodrug” of ethanol, urethane2.9, led
to the development of isoamylcarbamate 2.10, which in turn led to the
rst barbiturate, barbital2.11
. Fig. 2.4 An unsuccessful quinine synthesis founded the dye indus-
try. The chemical structures of many organic compounds were still
entirely unknown in the middle of the nineteenth century. The attempt
to prepare quinine via asimple route (upper reaction) could not have
worked. The oxidation of an impure aniline (below) gave mauveine
2.12 in 1856, which was used to dye silk abrilliant mauve color. It was
the rst synthetic dye!
2
Chapter • In the Beginning, There Was Serendipity
. Fig. 2.5 The laxative effect of phenolphthalein
became apparent while testing it as an additive for
cheap wines. The antisyphilis compound arsphenamine
2.14 (Salvarsan
an azo dye in which the –N═N– group was exchanged
for an –As═As– group
®
, here shown as monomer) is simply
still rather primitive. The intravenous application of
0.01–0.03 g to rabbits caused death “with loud shrieking, convulsions, and paralysis.” Vámossy then decided
to feed 1–2 g to arabbit and 5 g to a4 kg lap dog. Because these oral doses were all well tolerated, Vámossy
took 1.5 g of phenolphthalein himself, and afriend took
1.0 g. The effects were explosive: rumbling in the bowels, diarrhea, and for two additional days loose stools. It
was later established that 150–200 mg would have been
atherapeutic dose.
An entire range of antibacterial and antiparasitic
dyes are based on the work of Robert Koch (1843–
1910). He showed that bacteria and parasites accumulate dyes specically. Based on this, Paul Ehrlich (1854–
1915) hoped to kill pathogens selectively with suitably
chosen dyes. In 1891, he cured two mild cases of malaria
by treating the patients with methylene blue. In the following years he tested hundreds of different pigments,
and thousands more analogues were later synthesized
in the laboratories of Bayer and Hoechst. In 1909, Paul
Ehrlich pursued arational design when he exchanged
both of the nitrogen atoms of an –N═N– group of an
azo dye for arsenic atoms. Arsphenamine 2.14 (Salvarsan®, . Fig.2.5) was the rst effective compound to
treat syphilis: the rst chemotherapeutic. It became
an extraordinary economic success for the company
Hoechst.
The breakthrough with chemotherapeutics was made
by the physician Gerhard Domagk (1895–1964). At the
age of31, he took over the newly formed department
of experimental pathology at Bayer in Elberfeld. Azo
dyes bearing sulfonamide groups had already been designed by the chemists Fritz Mietzsch and Josef Klarer,
but they showed no in vitro activity; Domagk tested
these substances in streptococci-infected mice. By using
this model, he found the rst active substances in 1932.
Sulfamidochrysoidine 2.15 (Protonsil®, . Fig. 2.6),
adark-red dye that could treat even severe streptococci
infections, was rst made in 1935. The sulfonamides became world famous ayear later when the son of the US
president TheodoreD. Roosevelt, Jr. was treated with
such acompound to cure asevere sinus infection. But
even here afalse hypothesis led to success. It was not
the azo dye itself, but rather its metabolite sulfanilamide
2.16 that was effective. Sulfanilamide replaces p-amino-
benzoic acid 2.17 (. Fig.2.6), which is needed for the
. Fig. 2.6 The red azo dye sulfamidochrysoidine 2.15 is effective
only after cleavage to the colorless sulfanilamide 2.16, which is abacterial antimetabolite of p-aminobenzoic acid2.17
bacterial synthesis of the enzymatic cofactor, dihydrofolic acid (Sect.27.2).
2.4 Fungi Kill Bacteria and Help
with Syntheses
The discovery of the antibiotic effect of Penicillium notatum by Alexander Fleming (1881–1955) in 1928 is the
most famous example of aserendipitous discovery. Fleming noticed that aspoiled staphylococcus culture had been
contaminated with afungal infection. In the area around
the fungus, no bacteria could grow. Further investigations
showed that this fungus could also curb other bacteria.
Fleming called the still-unknown agent penicillin. It was
not until 1940 that it was isolated and characterized
by Ernst Boris Chain (1906–1979) and Howard Florey
(1910–1985). In 1941, an English policeman was the rst
patient to be treated with penicillin. Despite atemporary
improvement, and even though penicillin could be isolated from his urine, he died after afew days as no more
penicillin was available for his continued therapy. The
fungus Penicillium chrysogenum, which produces more
penicillin than Penicillium notatum and is easier to culti-
vate, was isolated from amoldy melon in Illinois. The tedious route to the structural elucidation of penicillin and
the successful work to systematically vary its structure
are scientic masterworks of the rst order. There were
even more difcult problems to conquer to optimize its
production and its biotechnological mass production. Today, the modied penicillins 2.18 and cephalosporins 2.19
. • The Synthetic Route Determines the Structure
. Fig. 2.7 Fleming’s accidental discovery of the antibiotic effects of
afungus has delivered awide palette of penicillins 2.18 and cephalosporins 2.19, each with different Rgroups
(. Fig.2.7), which make up abroad range of antibiotics
with outstanding bioavailability, are available. The newer
analogues have a broader spectrum of activity against
many pathogens and are distinguished by agenerally improved stability to the penicillin-degrading enzyme β-lactamase (Sect.23.7). Fleming was aresearcher to whom
Pasteur’s thesis “chance favors the prepared mind” fully
applies. One day in 1921 while working in his laboratory
with acold, he tried arather headstrong experiment. He
added adrop from his own nasal mucus to abacterial
culture and found afew days later that the bacteria had
been killed. This “experiment” led to the discovery of lysozyme, an enzyme that hydrolyzes the bacterial cell wall.
As atherapy, it is unfortunately unsuitable because it does
not attack most human pathogens.
Chance and afungus played an important role in the
industrial synthesis of corticosteroids. An important step
in the synthesis is the introduction of an oxygen atom at
aparticular position in the steroid scaffold, position11.
In 1952, chemists at the Upjohn company sought after
asoil bacteria that could hydroxylate asteroid in this
position. Just when they nally decided to set an agar
plate on the window bank of the laboratory, Rhizopus
arrhizus landed exactly there. This fungus transforms
progesterone (Sect.28.5) to 11α-hydroxyprogesterone.
With its help, the yield could be increased to 50%. The
closely related fungus Rhizopus nigricans even afforded
90% of the desired product.
2.5 The Discovery of the Hallucinogenic
Effect of LSD
In the 1930s, Albert Hoffmann (1906–2008) was working
on the partial synthesis of ergoline alkaloids at Sandoz.
In 1938, he wanted to nd away to transfer the respiratory and cardiovascular stimulatory effect of N,N-diethyl
nicotinamide 2.20 into this class of compounds. Analogous to 2.20, he prepared N,N-diethyl lysergamide 2.21
(. Fig.2.8) with the hope of maintaining the stimulatory circulatory and respiratory effects. The substances
showed no particular effect other than the experimental animals being agitated under anesthesia. Therefore,
they were not pursued at rst. Hoffman prepared the
substances for asecond time ve years later because he
. Fig. 2.8 N,N-Diethyl nicotinamide 2.20 is acentrally active deriva-
tive of nicotinic acid. Hofmann wanted to synthesize ageneral stimulant analogously by preparing the N,N-diethyl amide of lysergic acid.
The result was the hallucinogen lysergic acid diethyl amide 2.21 (LSD)
wanted to investigate them more thoroughly. Upon the
purication procedure and recrystallization, he reported
feeling “astrange agitation combined with aslight dizzi-
ness.” At home he fell into “anot-unpleasant inebriated
condition that was characterized by extremely animated
fantasies… after about 2hours, the condition went away.”
Hoffman suspected aconnection to the compounds he
prepared and conducted aself-experiment with 0.25 mg
afew days later. That was the smallest dose with which he
expected to see an effect. The outcome was dramatic, the
experience was the same as the rst time, but much more
intense. He had atechnician accompany him home on his
bicycle. During the ride, his condition took on athreatening form, and he fell into asevere crisis dominated
by dizziness and anxiety. The world took on agrotesque
form. Later it was determined that 0.02–0.1 mg is enough
to cause hallucinations. The substance was temporarily
marketed as Delyside® for use in psychotherapy and to
treat anxiety and compulsive disorders.
2.6 The Synthetic Route Determines
the Structure
The structure of the rst calcium channel blocker, verapamil 2.22 was determined by its synthesis (. Fig.2.9).
Verapamil counteracts the effects of β-adrenergic agonists, but it is not aβ-blocker. It was only after its introduction to the market that Albrecht Fleckenstein claried
its mode of action: it blocks the inwards membrane voltage-dependent ow of calcium ions through the calcium
channels (Sect.30.4) in cardiac and endothelial cells. The
hypotonic effect was initially seen as aside effect, but in
the following years it became the most important reason
for use. The second group of therapeutically important
calcium channel blockers, nifedipine 2.23 was inspired
by asynthetic principle, i.e., the Hantzsch synthesis of
dihydropyridines (. Fig.2.9) from 1882. Remarkably,
the pharmacological experiments on nifedipine had to be
carried out in adarkened room because of its photosensitivity. All the more reason to applaud its development
into amedicine despite this characteristic.
2
Chapter • In the Beginning, There Was Serendipity
. Fig. 2.9 Ferdinand Dengel, achemist at the former Knoll
AG, wanted to prepare acardiovascular drug by alkylating
anitrile. To avoid adouble substitution, he started with the
sterically demanding isopropyl group. The result was the
rst calcium channel blocker, verapamil 2.22. The isopropyl
group is the optimal alkyl group because it stabilizes the
biologically active conformation. The synthetic route played
an important role in the development of the second calcium
channel blocker, nifedipine 2.23. In 1948, Friedrich Bosser at
Bayer was given the task of nding new substances that dilate
the coronary arteries. After years of work, he turned in 1964
to the easily prepared dihydropyridines, which surprisingly
displayed the desired effects. In this case, the space-lling
nitro group promotes the biologically active conformation
(Sects.17.9 and30.4)
2.7 Surprising Rearrangements Lead
to Medicines
Leo Sternbach (1908–2005), achemist at Hoffman La
Roche, was involved in aprogram in the mid-1950s to nd
structurally novel tranquilizers. Sternbach remembered
asynthetic program on pigments from adecade before in
which N-oxide 2.24 (. Fig.2.10) was also prepared. Its
reaction with secondary amines delivered the expected
products, which were pharmacologically absolutely uninteresting. The work was practically ended in 1957, and
the laboratory was being cleaned up when it was noticed
that acrystalline base and its hydrochloride salt had precipitated from asolution. The substance was the product
of a reaction between N-oxide 2.24 and methylamine,
but it was never tested due to other priorities. The subsequent pharmacological testing convincingly showed
outstanding qualities. It was only later established that
an unexpected ring rearrangement reaction had occurred
to afford chlordiazepoxide 2.25 (Librium®, . Fig.2.10).
There are other examples of this sort. In 1974, W.Berney was working on spirodihydronaphthalenes 2.26
(. Fig.2.11) with the goal of preparing CNS-active substances. Upon acid treatment, he obtained acompound
that was highly potent in vitro and in vivo against aseries
of human pathogenic fungi in aroutine broad screening
at Sandoz Research Institute in Vienna. In 1985, the substance was introduced as naftine 2.27, and later amore
potent analogue, terbinane 2.28 (. Fig.2.11) followed.
Both substances showed apreviously unknown mode of
action. They damage the membrane of fungi in that they
block the ergosterol biosynthesis. This happens in avery
early step due to the inhibition of the enzyme squalene
epoxidase.
. Fig. 2.10 Treatment of 2.25 with methylamine delivers the rear-
rangement product chlordiazepoxide 2.25 (Librium®) instead of the
expected one. This rst test compound became the rst of the benzodiazepine class to be marketed
. Fig. 2.11 Instead of CNS activity, naftine 2.27, prepared from
spiro compound 2.26, is an antimycotic. Acomparison with the more
potent terbinane 2.28 shows that the phenyl group can advantageously be replaced with atert-butylethinyl group
. • Where Would We Be Without Serendipity?
2.8 A Long List of Accidents
The list of accidental discoveries, from which afew
are described here, can be extended ad innitum. Afew
more examples are briey mentioned without chemical
formulas.
Pethidine (Sect.3.3), the rst fully synthetic opiate
-
analgesic, was synthesized in the 1930s as part of an
anticonvulsives research program, by starting from
atropine.
The suitability of antihistamines for the prevention of
-
motion sickness was discovered in Boston because of
atreatment for askin rash. A patient reported that
her motion sickness, which always occurred when rid-
ing aBoston street car, went away. The “clinical trial”
was carried out in 1947 on hundreds of sailors on the
transatlantic voyage of the USNS General Ballou.
Haloperidol (Sect.3.3) was meant to be an analgesic;
-
it turned out to be aneuroleptic.
Imipramine is structurally very similar to the neuro-
-
leptic chlorpromazine (Sects.1.6 and8.5). Nonethe-
less, it has the opposite effect and is an antidepres-
sant.
Phenylbutazone was meant to be an additive used
-
to dissolve the anti-inammatory aminophenazone.
The substance turned out to be an anti-inammatory
agent itself as did its metabolite oxyphenbutazone.
An attempt to isolate the causative agent of bipolar
-
disorder from the urine of patients afforded only uric
acid. Because uric acid is poorly soluble, lithium urate
was tested. This led to the discovery of the antide-
pressant effect of lithium salts.
Clonidine was meant to be alocal treatment for the
-
runny nose that accompanies the common cold. In-
stead of the expected effect, aprofound hypotonic
effect was surprisingly found. Despite intensive struc-
tural variations, none of clonidine’s analogues have
surpassed its potency.
Levamisole was developed as abroad-spectrum an-
-
thelmintic (antiworm agent). Instead, an immuno-
modulatory effect was accidently found that now
stands in the therapeutic foreground.
Praziquantel was originally meant to be an antide-
-
pressant. Because of its high polarity, it cannot cross
the blood–brain barrier. An outstanding suitability
for the treatment of the tropical disease schistosomi-
asis (or bilharziosis) was found through broad biolog-
ical testing.
Achemist at Searle who was working on dipeptides
-
licked his ngers while ipping through the pages of
abook. The sweet taste that he noticed turned out
to be caused by the articial sweetener aspartame.
Saccharine was also found in avery similar way. In
the case of cyclamate, asmoker noticed asweet taste
to his cigarettes.
Even today when one would think that rational con-
-
cepts dominate drug research, the lucky accident
still helps to make “blockbusters.” In the pursuit of
aphosphodiesterase inhibitor to hinder the degradation of cyclic guanosine monophosphate (cGMP), an
improved treatment for angina pectoris was not found
(Sect.25.8). Instead it became conspicuous that the
male subjects in the clinical trial did not want to give
up the substance. After the side effect of astronger
penile erection was recognized, the side effect became the main effect. The compound sildenal was
marketed for the treatment of erectile dysfunction as
Viagra® and developed into abillion dollar product.
2.9 Where Would We Be Without
Serendipity?
In the English-speaking world, aword is in use that is
difcult to translate into other languages: serendipity.
This term, as an expression of alucky accident, was
coined by Sir Horace Walpole in 1754. It is derived from
aPersian fairytale in which three princes of Serendip
(earlier Ceylon, today Sri Lanka) have accidental and
unexpected luck and make interesting discoveries entirely analogously to the many examples in this chapter.
Serendipity has played an exceedingly important role
in general in science, and especially in drug research.
How would our modern medicine supply look without
all of these lucky accidents? By no means should an arbitrary approach be taken, and an accidental discovery
be counted upon. To the contrary, chemists and pharmacologists have always developed concrete ideas as to
how and why particular structural variations on alead
compound should be pursued. Some of these hypotheses
were correct, and others were false. One thing that they
always had in common that helped the researchers was
that when ahypothesis failed, or an unexpected result
was found, they recognized the potential consequences
of the result, drew the correct conclusions, and did the
right things. The following chapters will show numerous
examples of successful targeted drug design in cases in
which the correct working hypothesis was realized. The
search for anew active substance is, however, not aprocess that can be pushed through by apurely technically
oriented management. As a general rule, short-term
planning and bureaucratic control have only negative
consequences. On the other hand, the search for new
medicines requires aconcerted effort from many different groups of specialists who must work together in
asuitable organizational structure. The subsequent preclinical and clinical development of anewly found active
substance is an extremely expensive and time-consuming process that must be carefully planned, carried out,
and controlled. For this, other instruments are necessary
than are used for drug discovery.
Chapter • In the Beginning, There Was Serendipity
2
2.10 Synopsis
The history of early drug research is full of lucky ac-
-
cidents. Many active principles of substances were
discovered by serendipity, but mostly success can be
attributed to an outstanding researcher with a“pre-
pared mind” who observed important effects.
Dyes and pharmaceuticals, both developed in the
-
early stages of the up-coming chemical industry, espe-
cially stimulated each other in very fruitful synergies.
The discovery by Alexander Fleming of the rst anti-
-
biotic principle, the penicillins, as a defense mecha-
nism of afungus against bacteria is one of the most
famous examples of aserendipitous discovery.
The partial synthesis of ergoline alkaloids led to the
-
discovery of the hallucinogenic effects of LSD. In
those days, researchers frequently conducted self-ex-
periments to rst test active principle in humans.
Unexpected synthetic products, surprising structural
-
rearrangements, and initially false working hypothe-
ses produced new, pharmacologically interesting sub-
stances with surprising or outstanding qualities.
Even today, where rational concepts and the under-
-
standing of mode of action dominates drug research,
the lucky accident can still help to make “blockbust-
ers” as proven recently by the example of sildenal
(Viagra®).
L. H. Sternbach, The Benzodiazepine Story, Fortschr. Arzneimittel-
forsch., 22, 229–266 (1978)
A. Hofmann, LSD – mein Sorgenkind, dtv / Klett-Cotta (1993)
A. Stütz, Allylamine derivates—a new class of active substances in an-
tifungal chemotherapy, Angew. Chem. Int. Ed. Engl., 26, 320–328
(1987)
Bibliography and Further Reading
General Literature
A. Burger, A Guide to the Chemical Basis of Drug Design, John Wiley
& Sons, New York (1983)
G. de Stevens, Serendipity and Structured Research in Drug Discovery,
Fortschr. Arzneimittelforsch., 30, 189–203 (1986)
E. Verg, Meilensteine. 125 Jahre Bayer, 1863–1988, Bayer AG (1988)
R. M. Roberts, Serendipity. Accidental Discoveries in Science, John
Wiley & Sons, New York (1989)
W. Sneader, Chronology of Drug Introductions, in: Comprehensive
Medicinal Chemistry, C. Hansch, P. G. Sammes and J. B. Taylor,
Eds., Vol. 1, P. D. Kennewell, Ed., Pergamon Press, Oxford, pp.
7–80 (1990)
R. M. Restak, Receptors, Bantam Books, New York (1994)
H. Kubinyi, Chance Favors the Prepared Mind. From Serendipity to
Rational Drug Design, J. Receptor & Signal Transduction Re-
search, 19, 15–39 (1999)
T. A. Ban, The Role of Serendipity in Drug Discovery, Dialogues in
Clinical Neuroscience, 8, 335–344 (2006)
E. Hargrave-Thomas, B. Yu, J. Reynisson, Serendipity in anticancer
drug discovery, World J. Clin. Oncol., 3, 1–6 (2012)
Special Literature
A. Cahn and P. Hepp, Das Antifebrin, ein neues Fiebermittel, Centr-
alblatt für Klinische Medizin, 7, 561–564 (1886)
Z. von Vámossy, Ist Phenolphthalein ein unschädliches Mittel zum
Kenntlichmachen von Tresterweinen? Chemiker-Zeitung, 24,
679–680 (1900)
Classical Drug Research
Contents
3.1 Aspirin: ANever-Ending Story – 24
3.2 Malaria: Success and Failure – 26
3.3 Morphine Analogues: AMolecule Cut to Pieces – 30
3.4 Cocaine: Drug and Valuable Lead Structure – 32
3.5 H
3.6 Synopsis – 36
Antagonists: Ulcer Therapy Without Surgery – 33
2
Bibliography and Further Reading – 37
© The Author(s), under exclusive license to Springer-Verlag GmbH, DE, part of Springer Nature 2024
G. Klebe, Drug Design, https://doi.org/10.1007/978-3-662-68998-1_3