Transcript PowerPoint for the Session

Drug Discovery and
Development
How are drugs discovered and developed?
• 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 (cont.)
• 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 (cont.)
• 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
NH2
N
N
CH3
H3C
Imipramine
(a classical tricyclic antidepressant)
N
H
serotonin
F3C
HN
O
prozac
Choosing the Bioassay
• Definitions:
– In vitro: In an artificial environment, as in a test
tube or culture media
– In vivo: In the living body, referring to tests
conductedin living animals
– Ex vivo: Usually refers to doing the test on a
tissue taken from a living organism.
Choosing the Bioassay (cont.)
In vitro testing
• 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 (cont.)
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.
Finding the Lead (cont.)
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
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.
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
Next step: 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.
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
Example: 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
Clinical Trials
• Phase I: Drug is tested on healthy volunteers
to determine toxicity relative to dose and to
screen for unexpected side effects
Clinical Trials
• Phase II: Drug is tested on small group of patients
to see if drug has any beneficial effect and to
determine the dose level needed for this effect.
Clinical Trials
• Phase III: Drug is tested on much larger
group of patients and compared with existing
treatments and with a placebo
Clinical Trials
• Phase IV: Drug is placed on the market and patients
are monitored for side effects