INTRODUCTION TO

DRUG DEVELOPMENT
 What is a drug?
Drug is any substance presented for treating,
curing or preventing disease in human beings or in
animals. It may also be used for making a medical
diagnosis or for restoring, correcting, or modifying
physiological functions.
Where do drugs come from now?
Plants:
Digoxin (foxglove)
Belladonna (deadly nightshade)
Diamorphine (opium poppy)
Animal tissue:
Insulin, growth hormone
Synthetic manufacture:
Most modern medicines
 The Pharmaceutical Industry
• Develops, produces and markets drugs
licensed for use as medicine.
• Companies can deal in generic and / or brand
medications.
• Average cost to develop a successful new drug
£145million - £1.2 billion
• Subject to variety of laws and regulations.
 How are drugs
discovered & developed?
Stages in Drug Development
1 Drug discovery
Research & identification of compounds
2 Pre-clinical testing
Lab testing
3 Clinical trials
Testing on humans.
Flowchart for
evaluation
of new chemical
entities
 Drug Discovery
• From traditional remedies
– Aspirin
– Penicillin
 Aspirin – first synthetic drug
 (460-377 BC) Hippocrates Pain relief treatments with
powder made from the bark and leaves of the willow tree
 (1829) Johann Büchner Isolated pure salicin (salicylic acid
(1838))
 (1853) Charles Frederic Gerhardt first synthesised acetyl-
salicylic acid (ASA)
 (1898) Felix Hoffman Chemist at Bayer synthesized pure
sample of ASA
 (1899) Bayer receives patent for
Aspirin®
 Sales today exceed 50 billion pills
per year
 Penicillin – the first antibiotic
 Fleming was a researcher working in an untidy lab
 After returning from holiday he noticed that bacterial plates
had become contaminated with a fungus
 Bacteria were not present near the fungus on the plate
 He concluded that the fungus was secreting an antimicrobial
agent
 He extracted the agent and named it penicillin

Fleming was presented the Nobel Prize

for Medicine in 1945. He humbly said,
"Nature makes penicillin; I just found it."
• Choose a disease
• Choose a drug target
• Identify a “bioassay”
bioassay = A test used to determine biological
activity.
• Find a “lead compound”
“lead compound” = structure that has some
activity against the chosen target, but not yet
good enough to be the drug itself.
• If not known, determine the structure of the “lead
compound”
• Synthesize analogs of the lead
• Identify Structure-Activity-Relationships (SAR’s)
• Identify the “pharmacophore”
pharmacophore = the structural features directly
responsible for activity
• Optimize structure to improve interactions with
target
• Determine toxicity and efficacy in animal
models.
• Determine pharmacodynamics and
pharmacokinetics of the drug.
• Pharmacodynamics explores what a drug does to
the body, whereas pharmacokinetics explores
what the body does to the drug.
• Patent the drug
• Continue to study drug metabolism
• Continue to test for toxicity
• Design a manufacturing process
• Carry out clinical trials
• Market the drug
Choosing a Disease

• Pharmaceutical companies are commercial

enterprises
• Pharmaceutical companies will, therefore,
tend to avoid products with a small
market (i.e. a disease which only affects a
small subset of the population)
Choosing a Disease

• Pharmaceutical companies will

also avoid products that would
be consumed by individuals of
lower economic status (i.e. a
disease which only affects third
world countries)
 Choosing a Disease
Most research is carried
out on diseases which
afflict “first world”
countries: (e.g. cancer,
cardiovascular diseases,
depression, diabetes, flu,
migraine, obesity).
 Identifying a Drug Target

• Drug Target = specific macromolecule, or

biological system, which the drug will
interact with
• Sometimes this can happen through
incidental observation…
 Identifying a Drug Target
Example: In addition to their being able to inhibit the uptake
of noradrenaline, the older tricyclic antidepressants were
observed to “incidentally” inhibit serotonin uptake. Thus, it was
decided to prepare molecules which could specifically inhibit
serotonin uptake. It wasn’t clear that this would work, but it
eventually resulted in the production of fluoxetine (Prozac).

HO

N NH2
F3C
HN

CH3 O
N N
H
H3C
serotonin prozac

Imipramine
(a classical tricyclic antidepressant)
 The mapping of the human
genome should help!
• In the past, many medicines (and lead
compounds) were isolated from plant sources.

• Since plants did not evolve with human beings in

mind, the fact that they posses chemicals which
results in effects on humans is incidental.
• Having the genetic code for the production of an
enzyme or a receptor may enable us to over-
express that protein and determine its structure
and biological function. If it is deemed important
to the disease process, inhibitors (of enzymes), or
antagonists or agonists of the receptors can be
prepared through a process called rational drug
design.
 Simultaneously, Chemistry is Improving!

• This is necessary, since,

ultimately, plants and natural
sources are not likely to provide
the cures to all diseases.
• In a process called
“combinatorial chemistry” large
numbers of compounds can be
prepared at one time.
• The efficiency of synthetic
chemical transformations is
improving.
 Selectivity is Important!

e.g. targeting a bacterial enzyme, which is

not present in mammals, or which has
significant structural differences from the
corresponding enzyme in mammals
The Standards are Being Raised
• More is known about the biological chemistry
of living systems
• For example: Targeting one subtype of receptor
may enable the pharmaceutical chemist to avoid
potentially troublesome side effects.
 Choosing the Bioassay
In vitro tests
• Has advantages in terms of speed and requires
relatively small amounts of compound
• Speed may be increased to the point where it is
possible to analyze several hundred compounds in a
single day (high throughput screening)
• Results may not translate to living animals
 Choosing the Bioassay
In vivo tests
• More expensive
• May cause suffering to animals
• Results may be clouded by interference with
other biological systems
 Finding the Lead
Screening Natural Products
• Plants, microbes, the marine world, and
animals, all provide a rich source of
structurally complex natural products.
• It is necessary to have a quick assay for the
desired biological activity and to be able to
separate the bioactive compound from the
other inactive substances
• Lastly, a structural determination will need
to be made
 Finding the Lead
Screening synthetic banks
• Pharmaceutical companies have prepared
thousands of compounds
• These are stored (in the freezer!), cataloged
and screened on new targets as these new
targets are identified
 Finding the Lead
Using Someone Else’s Lead
• Design structure which is similar to existing lead, but
different enough to avoid patent restrictions.
• Sometimes this can lead to dramatic improvements in
biological activity and pharmacokinetic profile. (e.g.
modern penicillins are much better drugs than original
discovery).
 Finding the Lead
Enhance a side effect

O
H2N S NH2
O
sulphanilamide
(an antibacterial with the side effect of
lowering glucose levels in the blood and also
diuretic activity)

Cl N
O
O S O
O NH
NH S S
H2N O
NH O O
tolbutamide Chlorothiazide
(a compound which has been optimized to only (a compound which has been optimized to only display diuretic
lower blood glucose levels. Useful in the treatment activity.)
of Type II diabetes.)
Use structural similarity to a natural ligand

NH2 N(CH3)2

H
HO N
H3C S
O O
N N
H H

5-Hydroxytryptamine (5-HT) Sumatriptan (Imitrex)

Serotonin (a natural neurotransmitter Used to treat migrain headaches
synthesized in certain neurons in the CNS) known to be a 5-HT1 agonist
 Computer-Assisted Drug Design
• If one knows the precise molecular structure of the target
(enzyme or receptor), then one can use a computer to
design a perfectly-fitting ligand.
• Drawbacks: Most commercially available programs do
not allow conformational movement in the target (as the
ligand is being designed and/or docked into the active
site). Thus, most programs are somewhat inaccurate
representations of reality.
 Serendipity: a chance occurrence
• Must be accompanied by an experimentalist who
understands the “big picture” (and is not solely focused
on his/her immediate research goal), who has an open
mind toward unexpected results, and who has the ability
to use deductive logic in the explanation of such results.
• Example: Penicillin discovery
• Example: development of Viagra to treat erectile
dysfunction
 Finding a Lead
Sildenafil (compound UK-92,480) was synthesized by a
group of pharmaceutical chemists working at Pfizer's
Sandwich, Kent research facility in England.
It was initially studied for use in hypertension (high
blood pressure) and angina pectoris (a form of
ischaemic cardiovascular disease).
Phase I clinical trials under the direction of Ian Osterloh
suggested that the drug had little effect on angina, but
that it could induce marked penile erections.
Pfizer therefore decided to market it for erectile dysfunction,
rather than for angina.
The drug was patented in 1996, approved for use in erectile
dysfunction by the Food and Drug Administration on
March 27, 1998, becoming the first pill approved to treat
erectile dysfunction in the United States, and offered for
sale in the United States later that year.
It soon became a great success: annual sales of Viagra in the
period 1999–2001 exceeded $1 billion.
Finding a Lead

O
N
N
N

NH
O
O S
O
N

viagra
(Sildenafil)
Structure-Activity-Relationships (SAR’s)
Once a lead has been discovered, it is important to
understand precisely which structural features are
responsible for its biological activity (i.e. to identify the
“pharmacophore”)
The pharmacophore is the precise section of the
molecule that is responsible for biological activity
• This may enable one to prepare a more active molecule
• This may allow the elimination of “excessive”
functionality, thus reducing the toxicity and cost of
production of the active material
• This can be done through synthetic modifications
• Example: R-OH can be converted to R-OCH3 to see if O-
H is involved in an important interaction
• Example: R-NH2 can be converted to R-NH-COR’ to see if
interaction with positive charge on protonated amine is an
important interaction
Improve Pharmacokinetic Properties
• Improve pharmacokinetic properties.
pharmacokinetic = The study of absorption,
distribution, metabolism and excretion of a drug
(ADME).
 Metabolism of Drugs
• The body regards drugs as foreign substances,
not produced naturally.
• Sometimes such substances are referred to as
“xenobiotics”

•Body has “goal” of removing such xenobiotics from

system by excretion in the urine
•The kidney is set up to allow polar substances to
escape in the urine, so the body tries to chemically
transform the drugs into more polar structures.
 Metabolism of Drugs
• Phase 1 Metabolism involves the conversion of
nonpolar bonds (eg C-H bonds) to more polar
bonds (eg C-OH bonds).
• A key enzyme is the cytochrome P450 system,
which catalyzes this reaction:

RH + O2 + 2H+ + 2e– → ROH + H2O

Mechanism of Cytochrome P450
 Phase I metabolism may
either detoxify or toxify
• Phase I reactions produce a more polar
molecule that is easier to eliminate.
• Phase I reactions can sometimes result in a
substance more toxic than the originally
ingested substance.
• An example is the Phase I metabolism of
acetonitrile
 The Liver
Oral administration frequently brings the
drugs (via the portal system) to the liver
 Metabolism of Drugs
Phase II metabolism links the drug to still more
polar molecules to render them even more easy
to excrete
UDP Glucuronic Acid

Glucuronic Acid
HO O
O
P O
HO O
O P O O O
NH
glucuronosyltransferase O O
Drug
O O N enzyme HO R
HO HO O

OH HO OH
HO OH
OH
OH

More easily excreted than ROH itself

R OH

Drug
 Metabolism of Drugs
Another Phase II reaction is sulfation
(shown below)

NH2

N
O O N

O S O P O
O N
O-
N SO3-
R OH
O-
R O
Drug
Sulfated Drug
O OH (more easily excreted)
O P O-

O-

3'-Phosphoadenosine-5'-phosphosulfate
 Manufacture of Drugs
• Pharmaceutical companies must make a profit to continue to exist
• Therefore, drugs must be sold at a profit
• One must have readily available, inexpensive starting materials
• One must have an efficient synthetic route to the compound
– As few steps as possible
– Inexpensive reagents
• The route must be suitable to the
“scale up” needed for the
production of at least tens of
kilograms of final product
• This may limit the structural
complexity and/or ultimate size (i.e.
mw) of the final product
• In some cases, it may be useful to
design microbial processes which
produce highly functional,
advanced intermediates. This type
of process usually is more efficient
than trying to prepare the same
intermediate using synthetic
methodology.
 Toxicity
• Toxicity standards are continually becoming tougher
• Must use in vivo (i.e. animal) testing to screen for
toxicity
– Each animal is slightly different, with different metabolic
systems, etc.
– Thus a drug may be toxic to one species and not to another
 Thalidomide
Thalidomide was developed by German pharmaceutical company
Grünenthal. It was sold from 1957 to 1961 in almost 50 countries
under at least 40 names. Thalidomide was chiefly sold and
prescribed during the late 1950s and early 1960s to pregnant women,
as an antiemetic to combat morning sickness and as an aid to help
them sleep. Before its release, inadequate tests were performed to
assess the drug's safety, with catastrophic results for the children of
women who had taken thalidomide during their pregnancies.

Antiemetic = a medication that helps prevent and

control nausea and vomiting
 Birth defects
caused by use of thalidomide
 Thalidomide
From 1956 to 1962, approximately 10,000 children were born
with severe malformities, including phocomelia, because their
mothers had taken thalidomide during pregnancy. In 1962, in
reaction to the tragedy, the United States Congress enacted laws
requiring tests for safety during pregnancy before a drug can
receive approval for sale in the U.S.
O

N O

NH

O O

Thalidomide

Phocomelia presents at birth very short or absent long bones and

flipper-like appearance of hands and sometimes feet.
Only human studies can tell use how useful
and safe a drug is................

.....So clinical trials in human volunteers are needed.

Clinical Trials
 What are clinical trials?
• Research studies involving humans
• Used to determine if drug treatments are safe
and effective
• Are the safest and quickest way to find
treatments that work
 Types of clinical trails
• Treatment trials
• Prevention trials
• Screening trials
• Diagnostic trials
• Quality of life studies
• Genetics studies
 TREATMENT TRIALS
Testing
• New treatments
• New combination of drugs
• New approaches to Surgery
• New Radiation therapy
 PREVENTION TRIALS
Trying to find better ways to prevent
disease in people and to prevent disease
recurrence using
• Medicines
• Vaccines
• Vitamins
• Minerals
• Life style changes
 DIAGNOSTIC TRIALS

• To find better tests for diagnosis

of a disease
• To find better procedures for
diagnosis of a disease
 SCREENING TRIALS

To find out the best way to detect

certain diseases or conditions
 LIFE STYLE TRIALS
• Also called Supportive care trials
• Often employed for the chronically
ill patients
• They explore the ways to improve
comfort and
• to improve the quality of life
 Clinical trial protocol
• Strict scientific guidelines
– Purpose of study
– How many participants
– Who is eligible
– How study will be carried out
– What information will be gathered
– End points
 Clinical trials – phases
Stage 1 Stage 2 Stage 3
Drug Discovery Preclinical
Clinical trials
Phase I
Phase III
20-100 volunteers
1000-5000 volunteers

10,000
compounds 250 compounds 5 compounds

Phase II 1 approved
100-500 volunteers drug

6.5 years 7 years 1.5 yrs

Adapted from Pharmaceutical Research and Manufacturers of America

 Phases I trials
• Use healthy volunteers
• How does the drug affect the human body?
• Drug absorption, metabolism and excretion
• Preferred method of administration
• What dosage is safe?
 Phase II trials
• Use target patient group representative of those
likely to benefit from the drug.
• No pregnant women
• Does the drug have a beneficial effect on the
disease?
• Determine therapeutic dose range.
• Usually placebo controlled
• Conducted by experts in the disease field
 Phase III trials
• Obtains all data for regulatory agencies
• Often multi-centered, multinational
• Long term safety evaluated
• Is new drug better than standard?
 PHASE-IV TRIALS
• POST MARKETTING STUDIES
• TO KNOW ABOUT
1. DRUG RISKS
2. BENEFITS
3. OPTIMAL USE
DESIGN OF CLINICAL TRIAL
. Selecting the reference population

Selecting the experimental population

(Exclude Non-participants)
Selecting the study population (Participants)

Random allocation into

Intervention group Comparison group

Apply intervention No intervention

Uniform assessment of outcomes

 Research concepts-Placebo
An inactive pill, identical in appearance to the
treatment pill which is given to the control group.
Used to control for the placebo effect
Patient feels better due to belief in the treatment

Test pill Placebo

 Blind & Double Blind Trials
• A Blind Trial is a trial in which the patients do
not know if they are receiving the treatment or a
placebo.

• A Double Blind Trial is a trial in which the

patients and the researchers do not know who is
receiving the treatment.
 Randomised controlled trial
(RCT)
• Volunteers randomly assigned to new
treatment or best existing treatment
• Doctors have no say in who goes in which
group to reduce bias
 Participants in Clinical Trials
• Protocol sets out who can participate
• Use inclusion / exclusion criteria
• Factors that allow people in are inclusion
criteria (study for males)
• Factors used to reject are exclusion criteria
(may have history of illness)
 Clinical trials – the results

• Endpoint used to test trials success

• Ideally use a hard endpoint – cure from disease
• Statisticians analyse results – is A better than B?
• Only after analysis do you tell which is A and B.
 Drug Licensing
• Application submitted to Medicines and
Healthcare products Regulatory Agency
(MHRA)

• MHRA carry out pre-marketing assessment of

safety, quality and efficacy, examining all
research and results in detail.
 Drug Discovery—Convergence of Disciplines
Synthetic
Combinatorial Patent Law
Chemistry
Chemistry
Modelling
Novel
Intellectual Property
Molecule Physiology
Information Design Structural Biochemistry
Technology
Activity
Physiology
Safety Pharmaco- Physiology
Metabolism
dynamics Pharmacology
Safety
Assessment
In Vivo activity Pharmacokinetic Immunology
Properties DMPK

Pharmacology Behavior

Physical Physiology Enzymology

Pathology Physiology
Chemistry
 Drug Classification
Pure organic compounds are the chief source of agents for the cure,
mitigation or the prevention of disease.
These remedial agents could be classified according to their origin:
• Natural compounds: materials obtained from both plant and
animal, e.g. vitamins, hormones, amino acids, antibiotics,
alkaloids, glycosides…. etc.).

• Synthesis compounds: either pure synthesis or synthesis naturally

occurring compounds (e.g. morphine, atropine, steroids and
cocaine) to reduce their cost.

• Semi-synthesis compounds: Some compounds either can not be

purely synthesized or can not be isolated from natural sources in
low cost. Therefore, the natural intermediate of such drugs could
be used for the synthesis of a desired product (e.g. semi synthetic
penicillins).
 Drug Classification
Since there is no certain relation between chemical structure and
pharmacological activity therefore, it would be unwise to arrange all
drugs on the basis of their structures or origin. Thus, it is better to arrange
the drugs according to their medicinal use.
Drugs can be classified according to their medicinal uses into two main
classes:

I-Pharmacodynamic agents: Drugs that act on the various

physiological functions of the body (e.g. general anaesthetic, hypnotic
and sedatives, analgesic etc.).

II-Chemotherapeutic agents: Those drugs which are used to fight

pathogenic (e.g. sulphonamides, antibiotics, antimalarial agents, antiviral,
anticancer etc.).
 Drug Classification
Drugs can treat different types of diseases:

1-Infectious diseases: Born (transmitted) from person to person by

outside agents, bacteria (pneumonia, salmonella), viruses
(common cold, AIDS), fungi (thrush, athletes foot), parasites
(malaria)
2-Non-infectious diseases: disorders of the human body caused by
genetic malfunction, environmental factors, stress, old age etc.
(e.g. diabetes, heart disease, cancer. Haemophilia, asthma, mental
illness, stomach ulcers, arthritis).
3-Non-diseases: alleviation of pain (analgesic), prevention of
pregnancy (contraception) , anesthesia.
Other ways to categorise drugs
• What kind of molecule is it?

• What organ system (or what disease) is it for?

e.g., cardiac, psychotropic

• What parts of cells are affected?