Transcript Drug Discovery 3

• 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 (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
Finding the Lead (cont.)
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 (cont.)
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)
N
Cl
O
O
S
NH
O
NH
tolbutamide
(a compound which has been optimized to only
lower blood glucose levels. Useful in the treatment
of Type II diabetes.)
O
H2N
NH
S
S
O
O
O
Chlorothiazide
(a compound which has been optimized to only display diuretic
activity.)
Use structural similarity to a natural ligand
NH2
N(CH3)2
H
N
HO
H3C
S
O
N
H
5-Hydroxytryptamine (5-HT)
Serotonin (a natural neurotransmitter
synthesized in certain neurons in the CNS)
O
N
H
Sumatriptan (Imitrex)
Used to treat migrain headaches
known to be a 5-HT1 agonist
Finding the Lead (cont.)
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.
Finding a Lead (cont.)
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 (cont.)
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 (cont.)
O
N
N
N
NH
O
O
S
O
N
N
viagra
(Sildenafil)