1

Origins of Medicinal Chemistry

3500 BC - Sumerians report use of opium3000 BC - Chinese report use of ma huang (ephedra)

Greek culture:Hippocrates- followed the teachings ofAristotle; focus is on the soul.Galen- followed the teachings of Plato; focus ison experiment- believed the whole could beexplained by the parts

Renaissance period:Doctors were humanists- followers of Hippocrates-treat the soul and the body will heal. Initially, therewere no relationships with alchemy.

Paracelsus (1493-1541)- adopted teachings ofGalen; urged alchemists to discover the chemicalessence of herbal drugs and to develop chemicalmedicines- particularly those composed ofinorganic compounds (mercury, lead, antimony)

France (1560)- courts forbid the use of chemistryin medicines even though paracelsians are gainingin popularity - much controversy.

“The innumerable dissentions amongst the learned concerning the Arabicke andChymicke remedies at this day infinitely, and with opposite and contradictoriewritings, and invectives, burthen the whole world.” John Cotta (1612)

In 1658, Louis XIV is cured of chronicdigestive problems with an antimony purge-by 1666 the use of antimony and otherchemical medicines is approved by thecourts…..

2

In 1793, Faureroy & Vauquehin split from the monarchy-controlled bodies and establish the Ecole Supurieure dePharmacie- 1st to incorporate chemistry into thepharmacy curriculum. Develop research to find the activeprinciples in plant-based drugs.

1803 - Derosome isolates acrystalline salt from opium

1817 - Sertürner publishes work demonstrating that the narcoticprinciple of opium is basic (alkaline) and, thus, it will form saltswith acids- names the principle “morpheus”

Gay-Lussac predicts that other alkaline plant extractswill have useful medical properties- changes name ofmorpheus to morphine

1818 - Meissner proposes the general term alkaloids

N

N H

+ H-X

X-+

1853 - Henry How proposes that there are“functional groups” that can be chemicallymodified to alter reactivities….

morphineCH3I

quaternary salt

N N CH3 I-+

O

RO

HO

H

N

H

CH3

morphine R = Hcodeine R = CH3

Fraser and Brown make quaternary salts of many different alkaloids (i.e,morphine, strychnine, nicotine) and find that all exhibit curare-paralyzingactivities- propose that quaternary salts have curariform activity

O

O

O

H

N

H

CH3

O

H3C

O

H3C

diacetylmorphine

Stimulated by Fraser and Brown’s results, Alderand Wright treat morphine with various organicacids- synthesize diacetylmorphine.

1898- E. Merck of Darmstadt markets Dionin (ethylether of morphine) as a cough sedative

3

Pierce tests diacetylmorphine and finds it bemuch more potent than morphine- thus, smallerdoses can be given, which lowers toxicity.

1898- F. Bayer & Co. markets diacetylmorphine as a safer alternative to morphine-described as a “heroic drug” and given thename “heroin”. Within 4 years the use ofheroin was highly restricted

In 1820 Pelletier isolated quinine fromcinchona bark- by 1826 his group isproducing 3600 kg/yr of pure quinine,which is used instead of cinchonaextracts to treat malaria- birth of thepharmaceutical industry

N

NHO

H3CO quinine

1840’s - ether, chloroform, and nitrous oxide move frombeing party drugs to anesthetics - begins the search forother hypnotics1869 - Bucheim develops chloral hydrate, an oralcompound that exhibits hypnotic properties- heargues that it produces chloroform in the bloodwhile von Mering correctly postulates that itproduces trichloroethanol

HO CCl3

OH

HO-CH2CCl3

OSH

[O]

S

S

O O

O O

sulphonal

F. Bayer & Co. markets its firstsuccessful pharmaceutical,sulphonal, a hypnotic produced fromacetone.

Based on sulphonal, von Meringsuggests that a carbon withtwo ethyl groups should be agood hypnotic- makes diethylacetyl urea and thendiethylbarbituric acid

NH

O

N

O

H3C

diethyl acetylurea

HN

HN

OO

O

diethyl barbituric acid

O

H CCl3

N OO

ethyl ether

chloroform

nitrous oxide

4

1875- Carl Buss isolates salicylic acid from Spirea ulmariaand shows that it is an effective antipyretic- however, it isunpalatable and causes gastric distress.

1883- von Nencki makes a salicylate ester with phenol,salol- it has very poor solubility but it is bettertolerated. It is hydrolyzed slowly in the small intestineto give salicylic acid- the first sustained release drug

OH

O

OH

salicylic acidOH

O

O

salol (phenyl salicylate)

O

O

OH

acetyl salicylic acid

O

CH31890s - Hoffman at Bayer tests acetyl salicylicacid and finds it to be better tolerated- namesit aspirin as in “a” for acetyl and “spirin” forSpirea. It is rapidly hydrolyzed in the gut to giveactive salicylic acid- it is a “pro-drug”

NN

O

H3C

H3C

phenazone

Phenazone was synthesized in 1884 and was the most populardrug world-wide until it was taken over by aspirin in theearly 1900s- in addition to being an antipyretic, it alsocured headaches- a new market was born…

1880s- Kussmaul’s lab in Strasbourg is trying toeliminate intestinal worms with naphthalene- theyare mistakenly given acetanilide, which proves tobe an effective antipyretic

Bayer & Co. makes ethoxyacetanilide and marketsit as phenacetin

1893- Von Mering shows that para-hydroxyacetanilide(paracetamol) is an effective antipyretic and analgesic- it islater confirmed that paracetamol is the active metabolite ofphenacetin and acetanilide. Sterling-Winthrop markets it asPanadol (acetaminophen), which is now marketed as Tylenol

HN

O

CH3

acetanilide

HN

O

CH3

phenacetin

HN

O

CH3

paracetamolacetaminophen

O

CYP450

OH

CYP450

NCH3

CO2CH3

O

Ococaine

1884- Carl Koller- an ophthamologist- at the advice ofhis friend, Sigmund Freud, evaluates the use of cocaineas a topical anesthetic. Within a month of publishing hisresults it is being used world-wide. By 1887 problems arewidespread- stimulating the search for new anesthetics.

5

H2N

O

O

benzocaine

H2N

O

O

procaine

N

NH

O

O

tetracaine

N

NH

N

isogramine

NH

O

N

lidocaine

NH

O

bupivacaine

N

1902- Ritsert synthesizes benzocaine but it is toonon-polar to dissolve in water

Braun adds a polar amino group fromadrenaline to give procaine (novocaine)-addition of a butyl group gives tetracaine withgreatly extended duration

In 1935 isogramine is isolated and foundto be a very potent local anesthetic.

In 1946 Löfgren synthesizes lidocaine modeledafter isogramine- coins the concept of an“isostere”. This remains the most commonly usedlocal anesthetic. Addition of a butyl group givesthe long lasting (~ 8 hours) bupivacaine, which isused for epidural anesthesia during childbirth

O

RO

HO

H

N

H

CH3

morphine R = Hcodeine R = CH3

OH

O

OH

salicylic acidOH

O

O

salol (phenyl salicylate)

O

O

OH

acetyl salicylic acid

O

CH3

H2N

O

O

procaine

N

Questions to ponder…

Why do these two alcoholsdiffer in reactivity?

Why does this aminereact with CH3I?

Why does this OH groupreact with phenol to forman ester? While the otherreacts with acetic acid togive an ester?

Why is it that only thisnitrogen is charged?

HN

O

CH3

acetanilide

Why do CYP450 enzymesput an OH group only atthis position