Sart Exam 3 - Drug Discovery & Development

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Title: A Girl with a Watering Can
Artist: Pierre-Auguste Renoire

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How are Drugs Discovered & Developed?

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1. choose dz
2. choose drug target
3. identify 'bioassay'
4. fine 'lead' compound
5. synthesize analogs of the lead
6. identify structure-activity-relationships (SARs)
7. identify 'pharmacophore'
8. determine toxicity & efficacy in animal models
9. determine pharmacodynamics &
pharmacokinetics of drug
10. patent drug
11. continue to study drug metabolism
12. continue to test for toxicity
13. design manufacturing process
14. market the drug

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Bioassay

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test used to determine biological activity

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Lead Compound

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structure that has some activity against the chosen target, but not yet good enough to be the drug itself
-if not known, determine structure of the 'lead compound'

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Pharmacophore

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the structural feature directly responsible for activity
-optimize structure to improve interactions w/target

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Pharmacodynamics

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explores what a drug does to the body

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Pharmacokinetics

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explores what the body does to the drug

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Choosing a Dz

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1. Pharmaceutical companies are commercial
enterprises
2. most research carried out on dz's which
afflict 'first world' countries
3. the Orphan Drug Act of 1983

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Choosing a Dz: Pharmaceutical companies are commercial enterprises

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-avoid products w/small market (dz which only
affects small subset of population)
-avoid products that would be consumed by
individuals of lower economic status (dz which only
affects third world counties)

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Choosing a Dz: Most research carried out on dz's which afflict 'first world' countries

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examples: cancer, cardiovascular dz's, depression, diabetes, flu, migraine, obesity

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Choosing a Dz: Orphan Drug Act of 1983

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-passed to encourage pharmaceutical companies to
develop drugs to treat dz's which affect fewer than
200,000 people in the US
-companies who develop such drugs are entitles to
market it w/out competition for 7 yrs.
-considered significant benefit; standards for patent
protection more stringent

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Identify a Drug Target

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1. drug target
2. sometimes this can happen through incidental
observation
3. in past, many medicines (& lead compounds) were
isolated from plant sources
4. human genome mapping
5. simultaneously, chemistry is improving!

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Identify a Drug Target: Drug Target

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specific macromolecule, or biological system, which the drug will interact with

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Identify a Drug Target: Incidental Observation

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-example: fluoxetine
-tricyclic antidepressants: designed to inhibit uptake
of noradrenaline, were observed to 'incidentally'
inhibit serotonin uptake
-decided to prepare molecules which could
specifically inhibit serotonin uptake = eventually
resulted in production of fluoxetine (Prozac)

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Identify a Drug Target: Many medicines isolated from plant sources

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-plants did not evolve w/human beings in mind, the
fact they posses chemicals which result in effects on
humans in incidental
-foxglove = digitalis, cardiac glycosides =
antiarrhythmic

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Identify a Drug Target: Human Genome Mapping

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-having genetic code for production of an enzyme or
a receptor may enable us to over-express that
protein & determine its structure & biological
function
-if deemed important to dz process, inhibitors (of
enzymes) or antagonists/agonists of receptors can
be prepared through process = rational drug design
-ex: HER2 gene product overexpressed in 1/3 of
breast cancers --> herceptin

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Identify a Drug Target: Chemistry Improving

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-process called 'combinatorial chemistry' large
numbers of compounds can be prepared at one
time
-efficiency of synthetic chemical transformations
improving
-selectivity important
-targeting bacterial enzyme, not present in
mammals, with significant structural differences
from corresponding enzyme in mammals
-standards being raised
-more known about biological chemistry of living
systems
-ex: targeting one subtype of receptor may enable
pharmaceutical chemist to avoid potentially
troublesome side effects
-problems can arise:
-ex: chosen target, over time, may lose sensitivity
to the drug
-ex: penicillin-binding-protein (PBP) known to
primary target of penicillin in bacterial species
Staphylococcus aureus has evolved a mutant
form that no longer recognizes penicillin

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Choosing the Bioassay

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1. In vitro - artificial environment
2. In vivo - in living body
3. Ex vivo - test on tissue taken from organism
4. In vitro testing
5. In vivo tests

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Choosing the Bioassay: In vitro testing

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-advantages = speed & requires relatively small
amounts of compound
-speed may increase to point where its possible to
analyze several hundred compounds in single day
(high throughput screening)
-results may not translate to living animals

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Choosing the Bioassay: In vivo tests

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-more expensive
-may cause suffering to animals
-results may be clouded by interference w/other
biological systems

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Finding the Lead

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1. screening natural products
2. screening synthetic banks
3. using someone else's lead
4. enhance a side effect
5. computer-assisted drug design
6. serendipity: a chance occurrence

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Finding the Lead: Screening natural products

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-plants, microbes, marine world, & animals, all
provide rich source of structurally complex natural
products
-necessary to have quick assay for desired biological
activity & to be able to separate bioactive
compound from other inactive substances
-structural determination will need to be made

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Finding the Lead: Screening synthetic banks

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-pharmaceutical companies have prepared
thousands of compounds
-these are stored (in freezer!), cataloged & screened
on new targets as these new targets are identified

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Finding the Lead: Using someone else's lead

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-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 & pharmacokinetic profile (eg.
modern penicillin's better drugs than original
discovery)

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Finding the Lead: Enhance a side effect

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-Sulphanilamide = antibacterial w/side effect of
lowering bl. glucose levels & has diuretic activity
-Tolbutaminde = compound which has been
optimized to only lower bl. glucose levels
-useful in type II diabetes
-Chlorothiazide = compound optimized to only
display diuretic activity
-use structural similarity to natural ligand
-Serotonin (5HT) = synthesized in certain neurons
in the CNS
-Imitrex = sumatriptan = used to treat miraine
headaches known to be a 5HT1 agonist

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Finding the Lead: Computer-Assisted Drug Design

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-if one knows precise molecular structure of target
(enzyme/receptor) , one can use computer to design
perfectly-fitting ligand
-drawbacks: most commercially available programs
do not allow confrontational movement in target (as
ligand being designed and/or docked into active site)
-most programs somewhat inaccurate
representations of reality

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Finding the Lead: Serendipity

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ex: Slidenail
-synthesized by group of pharmaceutical chemists
working at Pfizer's sandwich, Kent research facility
-initially studied for hypertension & angina pectoris
(ischemic cardiovascular dz)
-phase 1 clinical trials suggested drug had little effect
on angina, but could induce penile erections
-marketed for penile dysfunction, not angina
-drug patented and became first pill approved for
erectile dysfunction = Viagra !

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Structure-Activity-Relationships (SAR's)

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-once lead discovered, imp. to understand precisely
which structural features are responsible for its
biological activity
-pharmacophore precise section of molecule
responsible for biological activity
-may enable to prepare more active molecule
-elimination of 'excessive' functionality, thus
reducing toxicity & cost of production of active
material
-can be done through synthetic modifications

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Improve Pharmacokinetic Properties

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1. Pharmacokinetics = study of ADME of a drug
2. Metabolism of Drugs
3. Phase 1
4. Phase 2
5. Phase 3

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ADME of drug

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-what the body does to the drug
-Absorption, Distribution, Metabolism, Excretion

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Improve Pharmacokinetic Properties: Metabolism of Drugs

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-body regards drugs as foreign substances, not
produce naturally ('xenobiotics')
-body has 'goal' of removing xenobiotics from
system by excretion in urine
-kidney set up to allow polar substances to escape in
urine, body tries to chemically transform drugs into
more polar structures
-drugs absorbed by sm. intestine & taken to liver via
portal vein
-liver can detoxify compounds before distribution
through circulatory system
-in liver, two main types of metabolism dealing w/
xenobiotics & 1/3 deals w/their transport

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Improve Pharmacokinetic Properties: Phase 1

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-results in sm. chemical changes making compound
more hydrophilic so it can be effectively eliminated
by kidneys
-reactions usually involve either adding or
unmasking hydroxyl, or some other hydrophilic
group (amine/sulphydryl group) - usually involve
hydrolysis, oxidation or reduction mechanisms
-cytochrome p450 superfamily
-may detoxify or toxify
-produce more polar molecule that's easier to
eliminate
-sometimes results in substance more toxic than
original ingested substance (ex: phase 1 metabolism
of acetonitrile)

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Cytochrome p450

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-superfamily - large & diverse
-group of enzymes that catalyze oxidation of organic
substances
-CYPs major enzymes involved in drug
metabolism & bioactivation
-mechanism of cytochrome p450:
-enzymes use haem iron to oxidize molecule,
often making them more water-soluble for
clearance
-achieve this by adding or unmasking polar
group

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Improve Pharmacokinetic Properties: Phase 2

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-metabolism links drug to more polar molecules to
render them more easily excretable
-reactions most commonly detoxify
-reactions usually occur at polar sites (COOH, OH)
-transferase enzymes responsible for most phase 2
reactions
-eg: uridine diphosphoglucuronsyl transferase (UGT),
N-acetyl transferase (NAT), glutathione S-transferase
(GST), & solphotransferase (ST)
-sulfation

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Improve Pharmacokinetic Properties: Phase 3

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-involves Drug Transporters - influence effect,
absorption, distribution, & elimination of drug
-drug transporters move drugs across cellular
barriers - can target sites of accumulation
-located in epithelial & endothelial cells of liver, GIT,
kidney, blood-brain barrier, & other organs

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Manufacturing of Drugs

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-Pharmaceutical companies must make profit
-may be useful to design microbial processes which
produce highly functional, advanced intermediates
-process usually more efficient than trying to
prepare same intermediate using synthetic
methodology
-toxicity
-example: Thalidomide

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Manufacturing of Drugs: Pharmaceutical companies must make profit

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-Readily available, inexpensive starting materials
-Must have efficient synthetic route to the compound
-As few steps as possible
-Route must be suitable to 'scale up' needed for
production of at least tens of kilograms of final
product
-may limit structural complexity and/or ultimate size
of final product

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Manufacturing of Drugs: Toxicity

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-standards continually becoming tougher
-must use in vivo testing to screen for toxicity
-each animal slightly different, w/different metabolic
systems, etc.
-drug may by toxic to one species & not another

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Manufacturing of Drugs: Thalidomide

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-German pharmaceutical company
-inadequate tests ran for safety
-sold to ~50 counties under 40 different names
-prescribed to preg. women as antiemetic (combat
morning sickness & sleep aid)
-horrible results: babies w/severe malformations =
phocomelia (short/absent long bones & flipper-like
appearance of hands/feet)
-Teratogenic = causing malformations in a fetus
-further research showed thalidomide good for
patients w/erythema nodosum leprosum (painful
skin condition w/leprosy) had pain relief w/this drug