Know Everything!!!!!!!!

•  Drug industry slides

•  Disease background
•  Enzyme mechanisms
•  Principles of drug design
•  Chemical reactions focused on
–  Separate slides for mechanisms of principles
–  You do NOT need to memorize the synthesis of drugs
•  You are expected to know all mechanisms
–  Write them out
•  You are expected to be able to answer all assignment
questions, and similar ones
–  Do each assignment more than once
–  Write down your answers
 Drugs
•  Chemical substances that are used in the
treatment, prevention or diagnosis of
disease
–  Chemical substances used to enhance or
improve quality of life
•  Types
–  Biopolymer
•  Protein, DNA, etc.
–  Small molecules
chemical activity that
is desirable
 History of Medicinal Chemistry
•  Earliest drugs were natural products
–  From plants, animals, insects, minerals
–  Secondary metabolites - substances that are
not directly required for metabolism
•  Communication (hormones, pheromones,
allomones)
•  Defense (poisons)
–  Plants, microorganisms
 Drugs and Poisons
•  Drugs
–  Produce desired (beneficial) biological effect
•  Poisons
–  Produce undesired (harmful) biological effect

Poison DOSE Drug

e

Pharmakon 3
meanings Greek
Remedy scapegoat
Poison
 Dosages
•  Normally we assume
–  low doses produce beneficial effects (drug)
–  high doses produce harmful effects (poison)

Not always the

case
 µ O n

Y Nu s P melts VX
O

LDsolskin 15mg xmin

m3
LDsolinhalation
10mg individual
compare to Sarin Q
LDsolskin
at O
L
1700mg
F
LDsolinhalation
35mg minted
 Dosages
•  Sometimes
–  low doses produce harmful effects (poison)
–  higher doses produce beneficial effects (drug)

e
g
Insulin
Human RBI
salt tolerate soo
Osmal
toxic 2300mmol
 Use of Natural Products
•  Identified by observation
–  Morphine (extracted from poppy
seeds)
•  Narcotic painkiller
•  Sedative
–  Cocaine (extracted from coca
leaves)
•  Topical painkiller
•  Stimulant
–  Ergotamine (ergot fungus from rye)
•  Smooth muscle contraction (induces
birth)
•  Hallucinogen (witchcraft and religious
rites)
Morphine
1522
opium elixir Landauer
10 ordered
1 opium
Friedrich Sert einen 1804
isolated morphine
1817 market morphine as a pani retainer
1827 commercial production
nerdy
dosage
treats
Problems with Traditional Medicine
•  Lack of objective testing
–  Anecdotal evidence (worked for me!)
–  Once evidence of efficacy is available, hard to
contradict
•  Many harmful remedies retained because of this
•  No control over dose
–  Plants/animals produce variable amounts of active
ingredient
–  Variations in preparation and administration
•  Ephedra
•  No instructions
–  Information passed verbally
–  Imprecise
–  Poor reproducibility
Development of Folk Remedies
•  Irrational methods
–  Healing and magic were often connected
–  Many folk remedies useless or dangerous
•  Doctrine of Signatures
–  Jakob Bohme, shoemaker and philosopher

0
(1575-1624)
–  God left clues to tell us how to use
things
–  This approach is/was used by almost
all cultures
 Doctrine of Signatures
•  Walnuts look like brains
–  Eating walnuts is good for brain health
•  Eagles have good eyesight and eat
fish
–  Eating fish is good for eyesight
•  Goats don t get plague
–  Eating goat kidney stones was used
as a cure for the plague
•  Sharks don t get cancer .
–  Sharks have cartilage whereas we
have bones
–  Shark cartilage used as cancer
treatment
–  Sharks get cancer
 Doctrine of Signatures
•  Mandrake roots look like
people
–  Roots used for many
medicinal and magical
purposes
–  Primary use was a cure
for demonic possession
 Doctrine of Signatures
•  Mandrake harvest
–  Used dogs to harvest
them
•  Protect against the
screaming
•  Ensure the magic is
preserved
 Ho Doctrine of Signatures
•  Rhino horn is a phallic
symbol
–  Powdered rhino horn used
in Chinese medicine as an
aphrodisiac
•  Mercury is a heavy liquid
–  People drink mercury as a
laxative
average horn Soo
500k
Rhinohorn 00 0001kg
2008 In demand for cancer treatment
 Doctrine of Signatures
•  Most remedies developed this way
were harmful, or at best were
harmless
–  Some actually worked!
•  Most did not give the desired benefit
–  Denied the patient proper treatment
•  Lack of rationality or evidence
–  Healer says it is good so it must be
–  No way to see if it works or to find
harmful treatments
•  Great opportunity for fraud
–  People will buy/sell anything
–  A sucker born every minute
 1800 s
•  Problems with drugs peaked in the 1800 s
–  No regulation
–  Increasing industrialization created big
markets
–  Aggressive marketing
–  Lots of opportunity for fraud
•  All these problems had/have always
existed, but there was a dramatic increase
in the 19th century
–  Partly because of improved science
 Science and Fraud
•  The emergence of science made people
trust claims
–  scientifically proven
–  patented
•  The emergence of science made it easier
to identify fraud
–  Before science, there was no way to know
 Science and Fraud
•  1862 – first analysis of sugar/alcohol
manipulation in wine
•  1873 – first analysis of morphine content
in opium
•  1874 – first experiments on the effects of
pesticides on humans
•  The drug business changed dramatically
during this period
Rachel Carson 1962 Si
ing
 Drug Industry During Late
1800 s
•  Fewer natural product and folk remedies were
used
–  Knowledge of useful remedies was lost
•  People tended to buy patent medicine
–  anything goes remedies sold on an industrial scale
–  wild west
–  Some patent medicine ingredients
•  Ethanol
treat
•  Opium to yellow
•  Arsenic used
malaria
• 
• 
Copper salts
p feet I
Mercury salts (HgCl – calomel)
•  Cyanide
1825 poem
 Patent Medicines 139 I 600
1948

children
•  Outrageous claims died
–  Cure everything
•  Little or no dosage information
•  No science or twisted science
•  No regulation
Radium
e William TA Bailey made Radithor Bailey
g 1918 1928 to cure impotence
laboratories

cares everything
Eden M Byers
1932
of Rad win Poisoning
1965 exhumed is
bodyof re buried
in Pb cotton
 Modern Drug Industry
•  1828 – Wöhler makes urea
–  Organic chemistry is born
•  1850 – Perkin makes mauve by accident
from coal tar
–  First synthetic dye
–  This launched the synthetic dye industry
–  Driven by the new science of organic
chemistry
–  Making dyes from coal tar
a NH 2
Los

mi I la in
Los
Manueline
 Synthetic Dye Industry
•  Peaked in the 1860 s
•  By 1880, dye companies were looking for
new markets. These companies:
–  Were research intensive
–  Operated on a scientific basis
–  Employed the best organic chemists
–  Had good manufacturing infrastructure
–  Had good marketing infrastructure
 Magic Bullet Concept
•  Paul Ehrlich 1854 1915
–  Observed that dyes could color some types of
cells but not others
•  Ex: gram –ve or gram +ve bacteria
–  Suggested that dyes might have selective
biological actions
–  Dyes could be medicines – if they affect some
cells but not others

named the modem

concept of chemotherapy
 Bayer Company
founded in 1863
•  Pioneered modern pharmaceutical system
–  Scientific research
–  Manufactured drugs chemically from simple
feed-stocks (coal tar)
–  Adopted marketing style of dye industry
•  Sell to doctors and pharmacists, not to the public
•  This is how modern ethical drug
companies work
 Story of Aspirin bitter nausea
tastes
•  Salicylic acid defenceman OH
P
–  Isolated from willow bark
CO2H
–  Made in bulk from coal tar
–  Sold as a pain killer and fever reducer
Salicin
a
I Ea E Egon
Co
Hf o
Cyp 450
OH

satiated
 Market Research
•  First Modern Drug Marketing OH
Strategy
–  A medical fad at the time was CO2H
the control of fever (treat
symptom, not disease)
–  Bayer played to this fad by
advertising salicylic acid as a
fever treatment to doctors and
pharmacists
•  Targeted marketing
•  Market research – sell what
people will buy
 Development of Aspirin
•  Bayer improved his drug using research
–  Salicylic acid was effective, but..
•  Tasted bad (bitter)
•  Irritated the stomach
–  The drug was improved by the study of
Structure Activity Relationships (SAR)
 SAR
•  Structure Activity Relationships
•  Process of drug optimization
•  Change structural features and observe
changes in properties (activity etc.)
 SAR of Salicylic Acid
important
•  Effective OH biological
•  Bitter taste
for
•  Stomach irritation
Activity
CO2H

•  Less Effective OMe

•  Taste acceptable (less bitter)
•  Less Stomach irritation
–  This was tested on fish gills (biological assay) CO2H

•  Effective (acetate removable) O O

•  Taste acceptable
•  Low Stomach irritation (fish gill assay) O
CO2H
 Aspirin
O O
•  The new compound was simple
•  Cheap to make (coal tar) CO2H
•  Bayer named the compound AspirinTablet
–  Marketing purposes
–  Trademarked the name (dye industry touch)
•  Sold to doctors and pharmacists only (dye
industry touch)
•  Developed through scientific study
–  SAR
–  Use of biological assay
 Synthesis of Aspirin
OH NaOH O O

CO2 O
Distilled from H
O
coal tar

O O OH H2SO4 OH
Aczo
O
CO2H CO2H
O
Kolbe
schmittRxy
 Board of Food and Drug
Inspection
•  From the dye industry was born the modern drug
industry (scientific)
•  Most drugs were still snake oil
•  To control the latter, the U.S. government
formed the Board of Food and Drug
Inspection (1907)
–  Set standards for drugs and food additives
–  Began with food
–  In 1912 began inspecting patent medicine
–  Concerned with labeling only
–  No regulation of therapeutic claims
–  No safety testing
 Sulfanilamide
•  By accident, a synthetic dye called
Prontosil was found to kill bacteria
–  Became the first antibiotic, used to treat Strep
throat in children H2N

N
N
NH2 NH2
S
O2

•  In 1937 it was found that prontosil was not

the active compound. Prontosil was
metabolized to Sulfanilamide in the body
H2N
–  First sulfa drug
NH2
S
O2
 H2N

Sulfanilamide S
O2
NH2

•  This drug was sold by the Massengil company

–  Pill or powder form
•  Because children did not like to take pills or
powder, a salesman convinced the company to
make a liquid formulation to expand their market
•  Harold Cole Watkins, a chemist at the company,
chose a formulation containing diethylene glycol
–  Good solvent
–  Sweet taste
–  Toxic – kidney and liver failure
•  No safety testing done
–  Not legally required
 Formulation
•  Ingredients added to the drug to improve
drug delivery excipient
–  Stabilizers, preservatives
–  Binders (pills) preventdegradation
758 are bases
–  Fillers (dilution) – easier to dose 206 are acids
–  Absorption enhancers 5 neutral

–  Flavoring, coloring
 Sulfanilamide
•  During 2 months in 1937, more than 100
children were killed by the liquid
formulation 260 children disabled
–  Destroyed liver and kidneys
•  Company refused to stop selling the drug
–  Claimed they had done nothing illegal
–  Never claimed responsibility
–  Watkins (chemist) killed himself when he
learned what the drug had done
 Sulfanilamide
•  Drug was finally forced off the
market by a labeling error
–  Drug was sold as an elixir
–  Legal definition of elixir is a substance
dissolved in ethanol
–  No ethanol was used, technically not an
elixir
•  Drug was sold in gallon jugs
•  Took 400 government employees 2
weeks to track down and confiscate
all the containers
 Sulfanilamide
"My chemists and I deeply regret the fatal
results, but there was no error in the
manufacture of the product. We have been
supplying a legitimate professional
demand and not once could have foreseen
the unlooked-for results. I do not feel that
there was any responsibility on our part."

Dr. Samual Evans Massengill

 Sulfanilamide
•  Because of this episode, the FDA (Food
and Drug Administration) was created
–  Ensure the safety of drugs
–  Animal testing was now required (safety only)
–  Clinical trials were done to follow safety in
humans
–  Directions for proper use were required on the
label
 O

Thalidomide N

O
O N O
H
•  Drug developed and sold as a sedative – 1957
–  Widely used in Europe
–  Initially, very few side effects
•  By 1962, it was clear that thalidomide was a
teratogen
–  Was never marketed in the U.S.
•  Approval paperwork was held up
•  Teratogenicity was discovered before
FDA approval was given
•  Phocomelia
 Teratogen
•  Substance causing birth defects
–  From Greek word teratos for monster
•  Thalidomide was safety tested in rats
–  Rats do not often give birth to deformed pups
•  Defective fetus is absorbed by the uterus
(digested)
•  During safety testing, no deformed pups or
stillbirths were noticed
–  In humans, problems with a fetus result in
miscarriage, stillbirth or birth defects
Francis
CDN pharmacologist
MSc McGill
PhD Univ 1936 1942
ofChicago
Faculty at Univ Chicago
1942 1960
1960 she was hired
by FDA
first evaluative thalidomide
received President's Award for
Distinguished Fed Carihair Service

retired at 90by old

TFI
yrs
died Aug7 2015
less than 24 hrs
after
being named to the order of
Canady
 Thalidomide
•  As a result of thalidomide episode, modern
safety standards were implemented
–  Safety testing must be done in at least 2
species
–  At least one of these must be a primate
–  Full pharmacokinetics must be supplied
showing that the drug is bioavailable during
the test,
–  Doses that are comparable to that to be used
clinically must be part of the regimen
 Rational Drug Design
•  Early drug discovery relied on random
screening (it still does)
•  Rational design of drugs
–  Based on knowledge of structure or function
–  Design a drug from first principles
•  Reactivity
•  Molecular shape and properties
–  Gertrude Elion (Nobel Prize 1988)
•  First to design a drug from first principles
 O

Acyclovir N NH
N N NH2
HO O
•  Designed to inhibit DNA synthesis in the Herpes
virus
–  Key requirement of the virus life-cycle
•  Drug resembles a nucleotide
–  Gets incorporated into growing DNA chain during viral
replication
–  No 3 hydroxyl group available to continue DNA chain
replication
–  Is only a substrate for viral enzyme
•  Designed using knowledge of how DNA
replication occurs
 Transcription (DNA Replication)
O Base
O O Base O Base
O O
Reverse Reverse
O O Transcriptase Transcriptase
P O O O O
O P P
O O O
O O
O Base
O Base O Base

P3 P3
OH O O
O O O O
O Base P O Base P
O O
O O
Base Base
O O
OH OH

OH O
O
P
O
O
O Base

OH
 Transcription (DNA Replication)
O Base
O O Base O Base
O O
Reverse Reverse
O O Transcriptase Transcriptase
P O O O O
O P P
O O O
O O
O Base
O Base O Base

P3 P3
OH O O
O O O O
O Base P O Base P
O O
O O
Base Base
O O
OH OH

OH O
O
P
O
O
O Base

OH
 Block Transcription
O Base O
O O Base
O
Reverse N NH
O O Transcriptase
P O O
O P N N NH2
O O
O HO O
O Base Base
O

P3
OH O O O
O Base P
O
O
Base
O

Drug resembles a nucleotide

No 3 hydroxyl group available to
continue DNA chain replication
Is only a substrate for viral enzyme
Specifically inhibits Viral DNA
replication and not Human DNA
replication
 Molecular Biology
•  Genetic engineering (1980 s)
–  Biggest impact has arguably been as a tool
for drug discovery
•  To improve a drug s properties (potency, side
effects, solubility etc.), need a readout of biological
activity (assay)
•  Previously, this was done by giving the drug to an
animal and looking for a readout
–  Complicated, many different factors involved
–  Difficult to extract information
–  Genetically engineered drugs are expensive
and specialized
•  High Profit Markets
 Molecular Biology
•  Can prepare, purify and analyze large
quantities of biological targets (proteins)
–  Easy to make assays
–  X-ray crystallography, NMR
–  Test drug action directly on purified target
•  Cleaner readout
•  Consistent readout (no variability from animal to
animal)
•  Faster SAR
•  Cheaper SAR (animals cost $$)
–  Rational drug design now possible
•  Antivirals, Gleevec, Hypertensives