A Short History of the Discovery and

Development of Modern
Pharmaceuticals
 Isolation of pure substances

• The development of modern pharmacotherapy

begins with the isolation of pure substances from
plants, through the use of solvent extraction at
the beginning of the 19th century
 Solvent Extraction

• German chemist (1747) Andreas Marggraf

observed that brandy could extract a
crystalline substance (sucrose) from beetroot
 Solvent Extraction

• Swedish chemist Carl Wilhelm Scheele (1742-

1786), applied solvent extraction to the
isolation of acids from plant juices
• He isolated citric, malic, oxalic, and gallic acids
in the 1780s.
 Where are we today?

• Solvent extraction continues to be a valuable part

of today’s isolation armamentarium, augmented
by column chromatography.
 Opium Plant

• Opium plant (Papaver somniferum) was used

in ancient civilizations (4000-1000 BCE) for
various medicinal purposes and in religious
ceremonies
 The Latex of the Poppy

• Opium is produced by drying the latex that

exudes from the capsules of the poppy.
• Around 1805-1820, a number of individuals simultaneously
reported the isolation of a crystalline, alkaline material
from the poppy latex.
• Friedrich Wilhelm Serturner (1783-1841) showed in 1811
that administration to dogs made the animals sleepy.
• However, the true power of morphine as a pain-
relieving agent only became apparent after the
invention of the hypodermic syringe by Alexander
Wood in 1853.
• Morphine found great utility in the civil
war, but, since ideal dosing was not
established, also caused many deaths.
• Additionally, many addicts were created
(and much quackery practiced).
• Even before the structure of the drug was known, a more
addictive derivative was generated by simply treating morphine
with acetic anhydride, to produce diacetylmorphine, or
diamorphine.
• The addictiveness of the new drug, heroin, was not immediately
appreciated, and it was marketed by Bayer Pharmaceutical.
 Sir Robert Robinson
1886-1975

• The chemical structure of morphine was not

established till 1923, when J. Masson Gulland
and Robert Robinson succeeded in
deciphering it.
Sir Robert Robinson was also responsible for
the invention of the ‘curly arrow’, used to
rationalize organic mechanisms.

… and he also founded the journal

Tetrahedron
 Where are we today?

• Morphine, and related opioid alkaloids,

remain the most effective method for the
treatment of severe pain.
It is known that the action of morphine is due to its
agonism of the mu (m) opioid receptor in the CNS.
• Shown above is an irreversible antagonist of this
receptor (structurally related to morphine)
• Crystallographic studies of the G-protein coupled
receptors (GPCRs) has been difficult, since they
are localized in membranes.
• Although there has been some recent success
Cinchona Bark
• As early as the 17th century, the Jesuits in
South America were using the bark of the
cinchona tree as a cure for malaria.
• The cure was brought to Europe, but was not immediately
accepted.
• Robert Talbor, a London apothecary published a small book
called A Rational Account of the Cause and Cure of Agues, and
eventually used the drug to cure several royals, including King
Charles II.
• Pierre Joseph Pelletier and Joseph Bienaimé
Caventou succeeded in isolating the active
principle, of the cinchona, quinine, in 1820.
• The purified quinine was much superior to
the nauseating unpalatable cinchona powder
and thus immensely successful.
• By 1826, Pelletier and Caventou had opened
two factories where they were processing
150,000 kg of cinchona bark yearly, yielding
around 3600 kg of quinine sulfate.
 Quinine

General structure of heterocycle

quinoline
• In 1907, Paul Rabe proposed the correct structure
of quinine (Rabe, P.; Ackerman, E.; Schneider, W.
Ber. 1907, 40, 3655), which was later confirmed
by a total synthesis by Robert B. Woodward.
• The formal synthesis of quinine,
published by R. B. Woodward and
W. E. Doering was the launch of
Woodward’s career as a master of
the art of organic synthesis, and
eventually led to a Nobel Prize.
 Where are we today?

Mefloquine
Chloroquine

• While quinine itself is no longer commonly used (due to

the evolution of parasitic resistance), several structurally
related derivatives are still commonly employed, both
prophylactically and for treatment of the disease.
 1900-1910

Drug Name: Epinephrine

Trade Name: Adrenalin® (Parke, Davis & Company)
Use: Hormone (vasopressor, stimulates heart muscle)
Use: Treatment of cardiac arrest, treatment of anaphylaxis,
treatment of sepsis, can be mixed with injectable forms of local
anesthetics
Jokichi Takamine was able to precipitate the free base of
adrenaline from aqueous solution by addition of aqueous
ammonia solution to raise the pH

He had developed a collaboration with the pharmaceutical

company Parke, Davis and Company.
 Where are we today?

Epinephrine is a powerful vasoconstrictor

In emergency situations, it can be injected intramuscularly or

intravenously to raise blood pressure or relieve anaphylaxis in
the case of severe allergic responses.
It is also injected subcutaneously to locally constrict blood
vessels and thus prolong the action of local anesthetics in dental
work, for example.
 1910

Drug Name: arsphenamine

Trade Name: Salvarsan
Use: antisyphillitic
• Some organoarsenic compounds (such as Atoxyl, shown
above) had shown activity in curing sleeping sickness, caused
by Trypanosoma brucei, transmitted by the tse-tse fly.
Paul Ehrlich was told that the causative agent of syphilis, the
spirochete Treponema pallidum, was similar to the trypanosome
Trypanosoma brucei, and encourage to try organoarsenicals as
curative agents.
Ehrlich initiated a program to make an extended library of
organoarsenic compounds.
The 606th compound he made showed activity against
Treponema pallidum and became the treatment for syphilis.
It was used from 1910 to 1944, when penicillin became the
treatment of choice for this disease.
 1912

Drug Name: Phenobarbital

Trade Name: Luminal
Use: Sedative, anticonvulsant
Use: Treatment of epilepsy
 1902
1864

Barbituric Acid

Barbituric acid was first prepared by Adolph von Baeyer in 1864, (on the feast of St. Barbara)
but it was not realized that this class of compounds had biological activity until Emil Fischer
showed diethylbarbituric acid (Barbital) could put dogs to sleep in 1904. This drug was used
to treat insomnia until 1950.
Phenobarbital was made by Emil Fischer in 1902,
and brought onto the commercial market as a
sedative by Bayer in 1912.
 Where are we today?

As sedatives, the barbituates were displaced by the

benzodiazepines in the 1950s, but they are still
utilized to treat seizures.
 1922

Drug Name: Insulin

Use: Hormone
Use: Treatment of diabetes mellitus
• Insulin is a peptide hormone that is secreted by the
pancreas.
• Insulin regulates the uptake of glucose from the blood.
• Insulin was the first hormone to be isolated.
In 1969, Dorothy Crowfoot Hodgkin used x-ray
crystallography to obtain the first crystal structure
of insulin. LINK
Cholesterol Penicillin

Vitamin B12

Dorothy Hodgkin had been very active in the field of x-ray

crystallography and had determined the structures of each
of the important molecules shown above.
Dorothy Hodgkin had earlier received the Nobel Prize in
Chemistry for her work on the x-ray crystallographic techniques.
 1935

In vivo

Metabolism

Protosil Sulfanilamide

Drug Name: Active form is Sulfanilamide

Trade Name: Prontosil
Use: Antiinfective
Before 1935, there was a desperate need for antibiotics
as bacterial infection represented a leading cause of
death.

The sulfa drugs represented the first highly effective

antibiotics and saved thousands of lives, including those
of Winston Churchill and Franklin Roosevelt Jr.
 Where are we today?

Sulfamethoxazole Trimethoprim

Although sulfa drugs are very old

antibiotics, they are still widely
used today.
One common combination includes
sulfamethoxazole and trimethoprim
to form the combination mixture
co-trimoxazole.
These two agents inhibit two enzymes that are
used in the bacterial biosynthesis of
tetrahydrofolate.
 1942

Drug Name: Penicillin

Use: Antiinfective
Where are we today?
It is now known that the target of the penicillins are the PBPs
(penicillin binding proteins) transpeptidases responsible for cross-
linking peptidoglycan strands.
 1957

Drug Name: Chlorpromazine

Trade Name: Thorazine
Use: Antipsychotic
Use: Treatment of schizophrenia
 1960

Norethynodrel Mestranol
(progestin) (estrogen, demethylated in liver)

Drug Name: Norethynodrel/mestranol

Trade Name: Enovid
Use: Hormone
Use: Birth Control (1st oral contraceptive)
 Where are we now?

Norethisterone acetate Ethynylestradiol

(Progestin) (Estrogen)

Combination progestin/estrogen oral contraception pills

remain popular, although there are alternatives.
Patches, which gradually administer the hormones
transdermally, are alternatives to oral formulations.
 1967

Drug Name: Propranolol

Trade Name: Inderal
Use: b-receptor antagonist (beta-blocker)
Use: Antihypertensive
• Propranolol was developed by James W. Black.
• While working for Imperial Chemical Industries, ICI, a British
chemical company, Black developed an interest in the way the
heart muscle responded to the hormone adrenalin
• He went to work to find a way to block the action of adrenalin and
developed the first of the ‘beta-blockers’ which block the action of
adrenalin at the beta-adrenergic receptors.
 1976

Drug Name: Cimetidine

Trade Name: Tagamet
Use: H2-receptor antagonist
Use: Treat heartburn, GERD, etc.
 1981

Drug Name: Captopril

Trade Name: Capoten
Use: Inhibitor of angiotensin converting enzyme
Use: Antihypertensive
 1987

Drug Name: Fluoxetine

Trade Name: Prozac
Use: Selective Serotonin Reuptake Inhibitor (SSRI)
Use: Antidepressant
 1997

Drug Name: Atorvastatin

Trade Name: Lipitor
Use: HMG-CoA reductase Inhibitor
Use: Cholesterol Reduction
 1997

Drug Name: Saquinavir

Trade Name: Fortovase
Use: HIV protease Inhibitor
Use: Treat HIV
 1998

Drug Name: Sildenafil

Trade Name: Viagra
Use: Inhibitor of PDE5
Use: Treat erectile disfunction
 1998

Drug Name: trastuzumab

Trade Name: Herceptin
Use: Monoclonal antibody to the HER2 protein
Use: Treat breast cancer
 1998

Drug Name: Imatinib

Trade Name: Gleevec
Use: Inhibitor of the ABL tyrosine kinase
Use: Treatment of selected cancers
 Readings

http://www.chemheritage.org/discover/chemistry-in-
history/themes/pharmaceuticals/restoring-and-regulating-the-bodys-
biochemistry/banting--best--collip--macleod.aspx

Bosch, F.; Rosich, L. The Contributions of Paul Ehrlich to Pharmacology: A Tribute on

the Occasion of the Centenary of His Nobel Prize, Pharmacology (2008) 82: 171-179.

160. The first sequence. Fred Sanger and insulin By Stretton Antony O W From
Genetics (2002), 162(2): 527-32.

Black, J. Reflections on drug research British Journal of Pharmacology (2010), 161:

1204-1216.
Homework Questions:

1. Explain how Paul Ehrlich’s early fascination with dyes led to his hypothesis
of the treatment of disease with a ‘magic bullet’. What is ‘side chain
theory’ and why was it important?
2. What did Ehrlich, Domagk, and Janssen share in common, both from a
scientific/investigation perspective, and secondly from a character
perspective?
3. Explain the underlying scientific importance of Fred Sanger’s successful
sequencing of insulin.