Drug Design and Development

Drugs produced by pharmaceutical industry have altered our way of life.

-

many life threatening diseases are now minor health concerns (polio, small
pox, TB, gastric ulcers, etc. A decade ago people with HIV infection usually
succumbed to AIDS within 2 years after the infection, while now, with regular
medication, they have a normal life expectancy.
Increase in life expectancy (more and more people are living into the 100s).
Improvement in quality of life (Viagra, birth control pills, treatments for
incontinence).

Principles of natural selection are being altered the most intelligent species (man) is
surviving and propagating.
Consequences of drug development
- overuse of antibiotics, bacterial resistance.
- More healthy elderly population, leading to diseases of the elderly
(cancer, autoimmune diseases, neurodegenerative and degenerative diseases
more people with these diseases means increased health care costs)

Is there still a need for new drugs? Of course, many diseases have no cure (common
cold), new diseases, and there is always room for better drugs.
Mapping of the human genome (what is it?) has opened new doors.

Drug discovery process has changed over the last couple of decades.
In the 1990s a lot of drug discovery and development was being done by BIOTECH
companies.
-

start-up companies, exploiting novel academic research for financial gain

small, funded by venture capitalists (VC)
aggressive, highly focused, less bureaucracy, more flexible
do or die projects.

In 1997, there were over 1100 Biotech companies most of them are gone now. The ones
that survived were taken up by larger companies. Venture capitalists are less interested in
investing in them as they are more risky, and take longer to yield profits when compared
to investment in internet companies (netscape, amazon, etc).

Another change due to Health Care Costs: federal and insurance company pressures that
require lower pricing of medicines that reduce profit margins.
Also, the cost of drug development has doubled every 4 years and is now almost $1.5
billion per drug!
Main outcome: Consolidation and outsourcing
1

Stages in Drug Discovery and Development

1.

Choose a disease! (A marketing decision!)

- one which requires new/improved drugs
- companies usually focus on first world diseases (migraine, depression, ulcers,
obesity, flu, cancer, cardiovascular diseases)
- third world diseases which can reduce life expectancy to 40 yrs are ignored
(now there is an increase in malaria research).

2.

Choosing a drug target:

- receptor, enzyme or nucleic acid (need to understand the disease and
understand what enzymes and receptors are involved) for eg. agonists of
serotonin receptors are useful for treatment of migraine while antagonists of
dopamine receptors are useful as antidepressants
- discovering a drug target
- earlier a drug target was surmised if a drug produced a biological
effect so the drug had to be found first! (natural products a hit and
miss affair.
- then the bodys own messengers were discovered which pointed the
fingers at particular targets.
- now with the mapping of the human genome, more and more new
targets are becoming available! For the first time there are more
targets than compounds to interact with them! The challenge is to find
compounds that will interact with them and find out what their
function is and whether they are suitable as drug targets.
The analogy we discussed in class - Indiana Jones with a key and a map to some temple
in the jungle follows the map, finds the exact door, opens the lock and gets the prize.
But if the forest has grown over the temple, he knows nothing of other doors and keys.
The modern Indiana Jones would clear up the forest and discover many doors. But he
doesnt yet have keys to open them.
So he could
1. Search for keys as in the past (screening)
2. Make a huge # of random keys (combinatorial chemistry)
3. Study the lock and see if a key can be designed (computer aided design)

Example of recently discovered novel targets: caspases enzymes that play a role in
inflammation and cell death (Dont forget that cell death is an important part of life!)
Agents that promote the activity of caspases and lead to more active cell death can be
used to treat autoimmune diseases, cancer, viral infections
Agents that inhibit caspases and reduce the prevalence of cell death can be used in the
treatment of trauma, neurodegenerative diseases and cell death arising from strokes.

Other issues to consider when choosing a drug target:

-

Target specificity and selectivity between species

The more selective the drug is for a target, the lower the chances of side
effects.
Eg, penicillin antimicrobial. Attacks enzyme involved in bacterial cell
wall biosynthesis no cell wall in mammals!
Sleeping sickness microorganism is propelled by a tail like flagellum
targeting proteins in the tail can give cure!

Target selectivity within the body

Target only one receptor and not other receptors
Target only one isoenzyme of an enzyme!

3.

Target particular organ!

Identifying a bioassay
Has to be simple, quick and relevant (toxicity vs antipsychotic)
so that a large # of compounds can be analyzed (high throughput screening).
In-vivo assays
Introduce the clinical condition in an animal so that the same symptoms
are produced. Then treat with drugs to see if they work.
Often transgenic animals are used genes are altered to produce human
enzyme or receptor, or become susceptible to a disease.
Problems:
Suffering to animals.
What does a negative result mean? Drug did not work or did it not reach
the target?
Different species react differently.
In-vitro assays
Testing specific cells or tissues or enzymes.
Results can be quantitated
But may not work in vivo.

4.

Finding a lead compound

Finding a compound that shows the desired pharmaceutical activity the level
may not be great and there could be undesired side effects.
A lead may be found by:

Screening of natural products

Studying medical folklore

3

Screening synthetic banks

Enhancing side effects of existing drugs (eg. sulfonamides are
antibacterial agents, but some of them could not be used because they
caused convulsions brought on by hypoglycemia led to antidiabetic
agent tolbutamide)
Starting from the natural ligand or modulator
Combinatorial synthesis
Computer aided drug design
Serendipity (needs a prepared mind - Explosives industry TNT caused
headaches due to dilation of blood vessels in the brain led to angina
treatment! Antioxidant used in rubber industry caused disgust for alcohol affected the oxidation of alcohol in the liver, buildup of acetaldehyde lead compound for treating alcoholism).
Computerized searching of databanks

After finding a lead compound, its affinity, and efficacy is assessed.

5.

Isolation, purification and structure determination of the lead compound.

If the structure of the active compound is not known (as is the case if the positive
result in the bioassay was obtained by using an extract from a marine organism,
for example the extract may contain several different compounds, only one of
which is active) it has to be isolated, purified, and its structure determined using
techniques such as HPLC, MS, NMR etc.

6.

Structure activity relationships (SARs): (Identifying the pharmacophore)

Once the structure of the lead compound and its biological activity is known, the
components of the structure that are essential for the activity have to be identified.
The minimum required structure is called a pharmacophore. A pharmacophore
was first defined by Paul Ehrlich in 1909 as "a molecular framework that carries
(phoros) the essential features responsible for a drugs (pharmacon's) biological
activity"
Different units and functional groups are added and removed from the
pharmacophore and their effect on the bioactivity is evaluated these studies are
call SAR studies.

7.

Pharmacokinetics and Metabolism

The most active drug in vitro may be useless in vivo. The clinically useful drug
has to travel through the body to reach the target it has to overcome many
barriers.
Drug has to survive long enough to have the desired effect, but may need to be
excreted once they have had the desired effect.
The metabolic enzymes in the body may break down the drug before it has a
chance to have effect.
Therefore the ADME (absorption, distribution, metabolism and excretion)
properties of the drug have to be determined.

8.

Synthesis issues
The eventual synthetic route followed to make a drug must be economically
viable. The most potent drug may not be selected due to cost of synthesis!
4

9.

Toxicological safety evaluation

Ames test one of the first tests for bacterial mutagenicity
Rising dose study on two mammalian species (one non-rodent) to se at what doses
toxicity is seen (7 days, 14 days, 28 days depending on anticipated exposure to
humans)
Chronic toxicity studies (6 12 months)
Finally a No Adverse Event Level (NOAEL) is determined.

10.

Clinical Development!!!
Investigational Exemption for a New Drug (IND) or [Clinical Trial Exemption
(CTX)- outside the US] has to be first filed with the FDA or equivalent
It documents the preclinical safety and efficacy studies, and is not formally
approved if no issues are raised in 30 days, the sponsoring company can start
human trials.
Phase I:
First time exposure to humans!
Healthy volunteers take the drug to test the drugs potency, pharmacokinetics,
sideeffects, maximum tolerated dose by the expected route of administration.
Sometimes patients are used for eg. with cytotoxic drugs for cancer!

Phase II:
Usually divided into a (a small group of patients to determine efficacy a major
go/no go milestone) and b (a larger 100 300 patients study, more
expensive).
Typically biochemical or physiologic indices are sought as objective endpoints for
drug efficacy.
Usually, double-blind studies, placebo, no-treatment controls, and positive
controls, etc.
Phase III:
Full scale evaluations (several 100 to 3000 patients) at several medical centers.
Can take anywhere between 2 8 years!
Compared with other available treatments or placebo (bias, race, sex,
psychological or real, ethical issues)
Dosage is very important at this stage because the data obtained at this stage is
what regulatory decisions are based.
Potential drug interactions are also assessed.
After this stage, the company can file for a New Drug Application with the FDA or a
Product License Application with the EU (many 1000s of pages).
FDA has 180 days to approve, approvable with minor modifications, or unapprovable
prioritized based on potential therapeutic gain (A, B and C)
5

Phase IV:
Drug placed in the market and can be prescribed, but is monitored. Side effects
may come after years, so in principle this should go on for ever!

Ethical issues:
Permission is mandatory, so how can you test with unconscious or mentally ill
patients who may benefit
Children cannot be included so licensing is for adults
Testing in third world countries raise other issues.

Patents:
Gives the patenter exclusive rights to manufacture a product for a certain length
of time and sell it at a certain price.
Why patent? - Needed to help the companies recoup their costs, and generate
sufficient profits for future research.
Patents have to be very specific, and regulations vary country by country so
depends on where you want to market.
Patent information should not have been previously revealed!
Usually runs for 20 years seems a long time, but it is not.
Patent laws are being reviewed genetic age gene targets are being patented
(this is like patenting gravity!)