Lecture 38 - Drug Discovery

Question 1

Outline the process of drug discovery

Answer 1

Therapeutic concept
Target identification
Target validation
Screening
Lead identification
Lead optimisation
Drug candidate

Question 2

What factors affect the choice of target disease / therapeutic area?

Answer 2

Money

• Unmet medical need
• Significant market
• Market share opportunity

Question 3

How is a target identified?

Answer 3

• Research biology of disease
• ‘omics’ based research
• Microarrays
• Based on plant / endogenous chemical

Question 4

How is the target validated?

Answer 4

• GFP and RFP of tumour cells in mice

- transgenic mice: (either KO or over expression) of the target in question

Question 5

What is screening?

What are some of the techniques used?

Answer 5

Trying to find the needle the haystack; ie a compound that has some affinity for the receptor in question

Question 6

What is lead identification?

Answer 6

We have found a chemical with some affinity, but we need to make it into a compound that meets all the requirements.

Going from a chemical to a lead compound

Question 7

What do we want our lead to be?

Answer 7

Selective
Potent
Molecular weight less than 500
Aqueously soluble
Can permeate cells
Metabolically stable
Sufficient half life

Question 8

What is lead optimisation?

Answer 8

Lead compound to drug candidate

Establishing that the drug meets all the requirements outlined

Question 9

What are the requirements of the drug candidate?

Answer 9

Aqeous solubility
No reactive / active metabolites
Metabolically stable
Ok half life

Question 10

What is the role of COX2?

Answer 10

Hyperalgesia in the brain

Macrophage activation, inflammation

Question 11

What is the role of COX1?

Answer 11

Platelet agglutination

Stomach cytoprotection

Question 12

What is the effect of NSAID on COX1 and COX2?

Answer 12

Blocks both COX1 and COX2

• Reduced inflammation
• Analgesia
• acid damage of stomach –> stomach ulcers
• blood thinner

Question 13

What is the effect of steroids on COX1 and COX2?

Answer 13

Blocks only COX2

Blocks transcription of the gene

Question 14

What is the effect of COX2 inhibitors?

Answer 14

Blocks only COX2

By blocking the protein product

Question 15

What is the problem with NSAIDs?

Answer 15

Not selective for COX2 - COX1 also affected.
Leads to negative side effects such as:
- stomach ulcers
- bruising

Question 16

What was the COX2 hypothesis?

Answer 16

That COX1 pathways were being negatively effected by NSAIDs

Question 17

What is the difference in the active sites of COX1 and COX2?

Answer 17

The active site for COX1 is smaller

Question 18

How was the COX problem overcome?

Answer 18

They came up with a new drug that was bigger
It could not fit in the active site of COX1

This is called a selective COX2 inhibitor

Question 19

What happened during the clinical trials of Rofecoxib?

Answer 19

After a year, there was a stark increase in the number of thrombotic events in the group taking the drug, compared to the control group.

Question 20

What happened in clinical trials of Celecoxib?

Answer 20

Increase in number of cardiovascular complications in the groups taking the drug

The more drug that was taken, more likely to have cardiovascular complications

Question 21

Describe a case of activity-based drug discovery

Answer 21

Cannabis
Widely used in the population (pseudo test subjects!)

We know from this use that the drug brings about certain effects

Used this knowledge to engineer cannabis into various drugs based on the effects we know it to have

Question 22

What are the effects of cannabis?

Answer 22

Appetite stimulation
Anti-nauseant
Analgesia
Sedation
Psychoactivity

Question 23

Which drugs arose from modification of cannabis?

What are they used for?

Answer 23

1. Nabilone - CB1 agonist
   Used for cancer patients undergoing chemo which causes nausea
2. Rimonabant - CB1 antagonist
   Used for obesity and hyperlipidaemia, as it is an appetite suppressor

Question 24

To which receptors does cannabis bind?

Answer 24

CB1

Question 25

What is Nabilone used for?

Answer 25

Nausea

Pain

Question 26

What is Rimonabant used for?

Answer 26

Obesity
Hyperlipideamia

Since it is an anoretic

Question 27

What are the side effects of Rimonabant?

Answer 27

Suicide

Depression

Question 28

What are the side effects of Nabilone?

Answer 28

Dependence

Interaction with depressants (eg alcohol)

Question 29

What is the ‘body’s own cannabis’?

To what do they bind?

Answer 29

Endocannabinoids

CB1
CB2

Question 30

Where are CB2 receptors commonly found?

Answer 30

Immune cells
Bone
PNS

Question 31

How could we get a drug based on cannabis that would have the negative psychoactive effects?

Answer 31

Block it from getting into the CNS

Question 32

How long does it take to get a drug on the market?

Answer 32

13.2 years

Question 33

Describe the financial journey of drug discovery

Answer 33

Expensive:

• preclinical development
• clinical development

Lucrative:
- Sales

Once it comes off patent, not so much money is made

Question 34

What aren’t new drug approvals rising at the same rate as technology advances?

Answer 34

Low fruit has been picked

It is harder to get drugs approved

Question 35

Give examples of theraputic areas with differing commercial potential

Answer 35

Malaria: small potential, because sufferers have no money

Hyperlipidemia: big potential market, because many people in the 1st world suffer from this

Pulmonary fibrosis: intermediate, growing market in the US, but historically a rare disease

Question 36

What is Lipinski’s rule of 5?

Answer 36

The drug must have a molecular weight less than 500

Because when the drug is larger than this, it is not well absorbed

Question 37

What is Rofecoxib?

Answer 37

It is a selective COX-2 inhibitor

Showed increase in incidence of thrombotic events in the trials

Question 38

What is a common side effect of chemotherapy?

Answer 38

Nausea

Question 39

How is nausea treated?

Answer 39

Nabilone

Question 40

Where are CB1 receptors found?

Answer 40

CNS