Lecture 38 - Drug Discovery Flashcards
Outline the process of drug discovery
Therapeutic concept Target identification Target validation Screening Lead identification Lead optimisation Drug candidate
What factors affect the choice of target disease / therapeutic area?
Money
- Unmet medical need
- Significant market
- Market share opportunity
How is a target identified?
- Research biology of disease
- ‘omics’ based research
- Microarrays
- Based on plant / endogenous chemical
How is the target validated?
- GFP and RFP of tumour cells in mice
- transgenic mice: (either KO or over expression) of the target in question
What is screening?
What are some of the techniques used?
Trying to find the needle the haystack; ie a compound that has some affinity for the receptor in question
What is lead identification?
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
What do we want our lead to be?
Selective Potent Molecular weight less than 500 Aqueously soluble Can permeate cells Metabolically stable Sufficient half life
What is lead optimisation?
Lead compound to drug candidate
Establishing that the drug meets all the requirements outlined
What are the requirements of the drug candidate?
Aqeous solubility
No reactive / active metabolites
Metabolically stable
Ok half life
What is the role of COX2?
Hyperalgesia in the brain
Macrophage activation, inflammation
What is the role of COX1?
Platelet agglutination
Stomach cytoprotection
What is the effect of NSAID on COX1 and COX2?
Blocks both COX1 and COX2
- Reduced inflammation
- Analgesia
- acid damage of stomach –> stomach ulcers
- blood thinner
What is the effect of steroids on COX1 and COX2?
Blocks only COX2
Blocks transcription of the gene
What is the effect of COX2 inhibitors?
Blocks only COX2
By blocking the protein product
What is the problem with NSAIDs?
Not selective for COX2 - COX1 also affected.
Leads to negative side effects such as:
- stomach ulcers
- bruising
What was the COX2 hypothesis?
That COX1 pathways were being negatively effected by NSAIDs
What is the difference in the active sites of COX1 and COX2?
The active site for COX1 is smaller
How was the COX problem overcome?
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
What happened during the clinical trials of Rofecoxib?
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.
What happened in clinical trials of Celecoxib?
Increase in number of cardiovascular complications in the groups taking the drug
The more drug that was taken, more likely to have cardiovascular complications
Describe a case of activity-based drug discovery
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
What are the effects of cannabis?
Appetite stimulation Anti-nauseant Analgesia Sedation Psychoactivity
Which drugs arose from modification of cannabis?
What are they used for?
- Nabilone - CB1 agonist
Used for cancer patients undergoing chemo which causes nausea - Rimonabant - CB1 antagonist
Used for obesity and hyperlipidaemia, as it is an appetite suppressor
To which receptors does cannabis bind?
CB1
What is Nabilone used for?
Nausea
Pain
What is Rimonabant used for?
Obesity
Hyperlipideamia
Since it is an anoretic
What are the side effects of Rimonabant?
Suicide
Depression
What are the side effects of Nabilone?
Dependence
Interaction with depressants (eg alcohol)
What is the ‘body’s own cannabis’?
To what do they bind?
Endocannabinoids
CB1
CB2
Where are CB2 receptors commonly found?
Immune cells
Bone
PNS
How could we get a drug based on cannabis that would have the negative psychoactive effects?
Block it from getting into the CNS
How long does it take to get a drug on the market?
13.2 years
Describe the financial journey of drug discovery
Expensive:
- preclinical development
- clinical development
Lucrative:
- Sales
Once it comes off patent, not so much money is made
What aren’t new drug approvals rising at the same rate as technology advances?
Low fruit has been picked
It is harder to get drugs approved
Give examples of theraputic areas with differing commercial potential
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
What is Lipinski’s rule of 5?
The drug must have a molecular weight less than 500
Because when the drug is larger than this, it is not well absorbed
What is Rofecoxib?
It is a selective COX-2 inhibitor
Showed increase in incidence of thrombotic events in the trials
What is a common side effect of chemotherapy?
Nausea
How is nausea treated?
Nabilone
Where are CB1 receptors found?
CNS
