Chapter 13. Drug Design and Discovery

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• Chapter 13. Drug Design and Discovery

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Drug Discovery
Average time to bring a drug to market is 12-15
years. Average cost is 600-800 million. For
every 20,000 compounds evaluated in animals, 10
make it to human clinical trials, of which 1 goes
to market.
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Clinical Trials
Phase I (3-18 months) - evaluates safety,
tolerability, pharmokinetics, and pharmacological
effects in 20-100 healthy volunteers Phase II
(1-3 years) - assesses effectiveness, determines
side effects and other safety aspects, clarifies
dosing in a few hundred patients Phase III (2-6
years) - establishes efficacy and adverse effects
from long-term use with several thousand
patients New Drug Application (NDA) submitted to
FDA (4-36 months) Phase IV - results after drug
is on market
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Drug Discovery
Drugs generally are not discovered directly
first a lead compound is identified.
Lead compound
Prototype having desired activity but also
other undesirable characteristics, e.g.,
toxicity, other activities, insolubility,
metabolism problems, oral bioavailability
Lead modified by synthesis

• to amplify desired activity

• to minimize or eliminate undesirable properties

Produces a drug candidate (compound worthy of
extensive biological, pharmacological, and animal
testing)
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Drug Discovery Without a Lead
Penicillins 1928 - Fleming
Bacteria lysed by green mold could not reproduce
effect - serendipity.

• mold spore contaminates culture dish
• left dish on bench top while on vacation
• weather was unseasonably cold
• particular strain of mold was a good penicillin
  producer

Could not get penicillin in a useful clinical form
1940 - Florey (Oxford)
Succeeded in producing penicillin in a useful
clinical form.
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Structure of penicillin elucidated in 1944 -
X-ray crystal structure by Dorothy Hodgkin
(Oxford)
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Lead Discovery
First a bioassay (or screen) is needed Means to
determine in vitro or in vivo, relative to a
control, whether the compound has the desired
activity and relative potency.
particular pharmacological effect (e.g.,
antibacterial effect) strength of the effect
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High-throughput Screens (HTS)
Very rapid, sensitive in vitro screens Can assay
100,000 compounds a day
1990 200,000 compounds screened per
year 1995 5-6 ? 106 compounds screened per
year 2000 gt 50 ? 106 compounds screened per
year in a large pharmaceutical
company
So far, no increase in rate of the number of
drugs coming on the market.
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Lead Discovery Approaches
1. Random screening - only approach before 1935
screen every compound you have still a useful
approach streptomycin and tetracyclines
identified in this way 2. Nonrandom (or Targeted
or Focused) screening - only screen compounds
related to active compounds 3. Drug metabolism
studies - metabolites produced are screened for
the same or other activities 4. Clinical
observations - new activities found in clinical
trials Dramamine tested as antihistamine
(allergy) - found to relieve motion sickness
Viagra tested as antihypertensive - found to
treat erectile dysfunction
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Lead Discovery Approaches (contd)
5. Rational approaches - identify causes for
disease states

• imbalance of chemicals in the body
• invasion of foreign organisms
• aberrant cell growth

Identify biological systems involved in disease
states use natural receptor ligand or enzyme
substrate as the lead a known drug also can be
used as a lead
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• 13.1. 1. The biological targets of drug action

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THE DRUG TARGET
Human genome 30,000
Disease modifying genes 3000
Druggable genome 3000
Drug targets 600-1500 2-3x current ?
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Schematic Model of NMDA receptor.
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Rational Drug Design
Chemical imbalances - antagonism or agonism of a
receptor enzyme inhibition Foreign organism and
aberrant cell growth - enzyme inhibition DNA
interaction
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Example of Rational Drug Design
Serotonin (2.19), a mediator of inflammation, was
used as the lead for the anti-inflammatory drug
indomethacin (2.20).
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Problems with Rational Approaches
Cannot predict toxicity/side effects. Cannot
predict transport/distribution. Cannot predict
metabolic fate.
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Lead Modification
Pharmacodynamics receptor interactions -
structure of lead is similar to that of the
natural receptor ligand or enzyme
substrate Pharmacokinetics ADME - absorption,
distribution, metabolism, excretion depends on
water solubility and lipid solubility
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Identification of the Active Part of the Lead
First consider pharmacodynamics Pharmacophore -
the relevant groups on the compound that interact
with the receptor and produce activity Auxophore
- the rest of the molecule
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Structure-Activity Relationships (SARs)
1868 - Crum-Brown and Fraser Examined
neuromuscular blocking effects of a variety of
simple quaternary ammonium salts to determine if
the quaternary amine in curare was the cause for
its muscle paralytic properties. Conclusion the
physiological action is a function of chemical
constitution
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Structurally specific drugs (most drugs) Act at
specific sites (receptor or enzyme) Activity/poten
cy susceptible to small changes in structure
Structurally nonspecific drugs No specific site
of action Similar activities with varied
structures (various gaseous anesthetics,
sedatives, antiseptics)
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Example of SAR
Lead sulfanilamide (R H)
Thousands of analogs synthesized From clinical
trials, various analogs shown to possess three
different activities

• Antimicrobial
• Diuretic
• Antidiabetic

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SARGeneral Structure of Antimicrobial Agents
R SO2NHR?, SO3H

• Groups must be para
• Must be NH2 (or converted to NH2 in vivo)
• Replacement of benzene ring or added
  substituents decreases or abolishes activity
• R can be , , ,
• (but potency is reduced)
• R SO2NR?2 gives inactive compounds

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Structural Modifications
Increase potency Increase therapeutic index -
measure of the ratio of the concentration of a
drug that gives undesirable effects to that which
gives desirable effects e.g., LD50 (lethal
dose for 50 of the test animals) ED50
(effective dose to give maximum effect in 50
of test animals)
Therefore, want LD50 to be large and ED50 to be
small. The larger the therapeutic index, the
greater the margin of safety. The more life
threatening the disease, the lower is an
acceptable therapeutic index.
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Types of Structural Modifications
Homologation - increasing compounds by a constant
unit (e.g., CH2)
Effect of carbon chain length on drug potency
Figure 2.3
Pharmacokinetic explanation Increasing chain
length increases lipophilicity and ability to
cross membranes if too high lipophilicity, it
remains in the membrane Pharmacodynamic
explanation Hydrophobic pocket increases binding
with increasing length too large and does not
fit into hydrophobic pocket
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Branched chain groups are less lipophilic than
straight chain groups.
in throat lozenges
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Chain Branching
Often lowers potency and/or changes activity
interferes with receptor binding
10-Aminoalkylphenothiazines (X H)
R CH2CHNMe2 promethazine antispasmodic/antihist
amine activities predominate
CH3
R CH2CH2CH2NMe2 promazine greatly reduced
antispasmodic/antihistamine activities greatly
enhanced sedative/tranquilizing activities
R CH2CHCH2NMe2 trimepazine reduced
tranquilizing activity enhanced antipruritic
(anti-itch) activity
All bind to different receptors
CH3
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Ring-Chain Transformations
Transformation of alkyl substituents into cyclic
analogs, which generally does not affect potency.
(2.40, X Cl, R CH2CH2CH2NMe2) and (2.40, X
Cl, R CH2CH2CH2N ) have equivalent
tranquilizing effects
Chlorpromazine (antipsychotic)
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Trimepazine (2.40, X H, R )
and Methdilazine (2.40, X H, R )
have similar antipruritic (anti-itch) activities.
Ring-chain transformation can have
pharmacokinetic effects, such as increased
lipophilicity or decreased metabolism.
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Trimepazine (2.40, X H, R )
and Methdilazine (2.40, X H, R )
have similar antipruritic (anti-itch) activities.
Ring-chain transformation can have
pharmacokinetic effects, such as increased
lipophilicity or decreased metabolism.
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Bioisosterism
Bioisosteres - substituents or groups with
chemical or physical similarities that produce
similar biological properties. Can attenuate
toxicity, modify activity of lead, and/or alter
pharmacokinetics of lead.
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Classical Isosteres
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Non-Classical Isosteres
Table 2.3
Do not have the same number of atoms and do not
fit steric and electronic rules of classical
isosteres, but have similar biological activity.
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Examples of Bioisosteric Analogues
Table 2.4
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Ionization has profound effect on lipophilicity
(pharmacokinetics) and interaction with a
receptor (pharmacodynamics). Neutral form crosses
membranes, then re-establishes equilibrium with
ionized form on other side. Ionized molecules
that did not cross the membrane re-establish
equilibrium with the neutral form, which can
cross the membrane. At neutral pH there is a
mixture of neutral and cationic forms.
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The uricosuric drug phenylbutazone has a pKa of
4.5 and is active as an anion.
Scheme 2.9
The pH of urine is 4.8. Sulfinpyrazone has a
pKa of 2.8
Therefore all in anionic form. 20 times more
potent than phenylbutazone
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In a cell-free system (no membranes), the
antibacterial activity of sulfamethoxazole is
directly proportional to the degree of ionization
(pharmacodynamics).
Scheme 2.10
In intact cells, where a drug must cross a
membrane to get to the site of action, the
antibacterial activity is proportional to its
lipophilicity (neutral).