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.

• The chemical structure of morphine was not established till 1923, when J. Masson Gulland and Robert Robinson succeeded in deciphering it.

Sir Robert Robinson1886-1975

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 () 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.

• 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.

Quinine

General structure of heterocycle quinoline

• 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?

• 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.

Mefloquine

Chloroquine

1900-1910

Drug Name: EpinephrineTrade 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: arsphenamineTrade Name: SalvarsanUse: 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: PhenobarbitalTrade Name: LuminalUse: Sedative, anticonvulsantUse: Treatment of epilepsy

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.

1902

Phenobarbital was made by Emil Fischer in 1902, and brought onto the commercial market as a sedative by Bayer in 1912.

As sedatives, the barbituates were displaced by the benzodiazepines in the 1950s, but they are still utilized to treat seizures.

Where are we today?

1922

Drug Name: InsulinUse: HormoneUse: 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

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.

Cholesterol Penicillin

Vitamin B12

Dorothy Hodgkin had earlier received the Nobel Prize in Chemistry for her work on the x-ray crystallographic techniques.

1935

Drug Name: Active form is SulfanilamideTrade Name: ProntosilUse: Antiinfective

In vivo

Metabolism

Protosil Sulfanilamide

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?

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.

Sulfamethoxazole Trimethoprim

These two agents inhibit two enzymes that are used in the bacterial biosynthesis of tetrahydrofolate.

1942

Drug Name: PenicillinUse: 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: ChlorpromazineTrade Name: ThorazineUse: AntipsychoticUse: Treatment of schizophrenia

1960

Drug Name: Norethynodrel/mestranolTrade Name: EnovidUse: HormoneUse: Birth Control (1st oral contraceptive)

Norethynodrel (progestin)

Mestranol (estrogen, demethylated in liver)

Where are we now?

Combination progestin/estrogen oral contraception pills remain popular, although there are alternatives.Patches, which gradually administer the hormones transdermally, are alternatives to oral formulations.

Ethynylestradiol(Estrogen)

Norethisterone acetate(Progestin)

1967

Drug Name: PropranololTrade Name: InderalUse: -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: CimetidineTrade Name: TagametUse: H2-receptor antagonistUse: Treat heartburn, GERD, etc.

1981

Drug Name: CaptoprilTrade Name: CapotenUse: Inhibitor of angiotensin converting enzymeUse: Antihypertensive

1987

Drug Name: FluoxetineTrade Name: ProzacUse: Selective Serotonin Reuptake Inhibitor (SSRI)Use: Antidepressant

1997

Drug Name: AtorvastatinTrade Name: LipitorUse: HMG-CoA reductase InhibitorUse: Cholesterol Reduction

1997

Drug Name: SaquinavirTrade Name: FortovaseUse: HIV protease InhibitorUse: Treat HIV

1998

Drug Name: SildenafilTrade Name: ViagraUse: Inhibitor of PDE5Use: Treat erectile disfunction

1998

Drug Name: trastuzumabTrade Name: HerceptinUse: Monoclonal antibody to the HER2 proteinUse: Treat breast cancer

1998

Drug Name: ImatinibTrade Name: GleevecUse: Inhibitor of the ABL tyrosine kinaseUse: 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.