Transcript Drug Discovery and Development

Drug Discovery and
Development
How are drugs discovered and developed?
Basic Steps
• 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)
• Structure-Activity-Relationship (SAR) = How does
the activity change as structure is systematically
altered?
• 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.
Basic steps (cont.)
•
•
•
•
•
•
Patent the drug
Study drug metabolism
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).
The Orphan Drug Act
• The Orphan Drug Act of 1983 was passed
to encourage pharmaceutical companies to
develop drugs to treat diseases which
affect fewer than 200,000 people in the US
• Under this law, companies who develop
such a drug are entitled to market it without
competition for seven years.
• This is considered a significant benefit,
since the standards for patent protection
are much more stringent.
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