Drug Discovery And Development

Question 1

What do medicinal chemists consider in Stage 1 of drug discovery?

Answer 1

Disease? - western world
Drug target? - proteins, receptors…
Identify bioassay

Find ‘ hit’ compound
Isolate and purify hit compound
Determine structure of lead compound

Question 2

What do medicinal chemists consider in Stage 2 of drug discovery?

Answer 2

Identify SARs
Identify pharmacophore - what’s important?
Improve PK properties

Patent drug
Study ADME
Test for toxicity

Question 3

What do medicinal chemists consider in Stage 3 of drug discovery?

Answer 3

Designing manufacturing process - ChemEng
Clinical trials
Market the drug

Question 4

What are the features of In Vitro testing?

Answer 4

Involves isolated cells/tissues in cultured solutions - test tube

Enzyme inhibitors can be tested on purified solutions - so can receptor agonists/antagonists.

Question 5

How are In Vitro tests usually measured to determine a drugs effectiveness?

Answer 5

A physiological end-point is usually measured eg. Examining drug effect on inhibition of contraction of smooth muscle.

In Vitro activity is usually expressed as IC50 or EC50 concentrations - inhibitory or effective.

Question 6

What is High Throughput screening (HTS)?

Answer 6

Automated and miniaturised in vitro tests on genetically modified cells

Question 7

What does HTS involve?

Answer 7

Involves testing of thousands of compounds against many biochemical targets.

Usually coupled with combinatorial chemistry

Question 8

What’re the features of In Vivo testing?

Answer 8

Involves inducing a clinical condition to an animal to produce observable conditions.

Question 9

What’s an example of In Vivo testing?

Answer 9

Infecting mice with parasites in antimalarial drug discovery

Drug is assessed by either; the ability to clear parasites or the ability to prolong mouse survival.

Question 10

How does genetics impact in Vivo testing?

Answer 10

Now possible to produce transgenic animals - replace mouse genes with human genes, hence mouse host produces human receptor or enzyme equivalents.

Question 11

What’re the most common ways of discovering a lead compound?

Answer 11

Random screening of synthetic ‘banks’

Existing drugs - ‘Me too’ drugs

Starting from natural ligand

Screening natural materials

Question 12

What’s an example of a ‘Me too’ drug?

Answer 12

Antihypertensive drug captopril - leading to cilazapril and enalapril

Found by sufficiently modifying a competitors lead compound to get around patent restrictions

Question 13

What is the SAR for penicillin?

Answer 13

Amide, free carboxylic acid and bicyclic ring structure are all essential for the function of penicillin

Stereochemistry of both H’s is also essential

Question 14

What function does the bicyclic ring have in the function of penicillin?

Answer 14

Bicyclic ring increases strain of ß-lactam ring - more reactive

Therefore more strain means a more potent analogue - however too strained = unstable.

Question 15

What’re the pharmacophore groups of penicillin?

Answer 15

Bicyclic ring, ß-lactam ring, carboxylic acid and side-chain amide groups are all classed as pharmacophoric groups

Question 16

Why is penicillin so acid sensitive?

Answer 16

Bicyclic ring system strain means acid catalysed ring opening occurs

ß-lactam carbonyls are very reactive

The side chain can cleave the ß-lactam ring - N lone pair donates and amide oxygen attacks ß-lactam oxygen.

Question 17

How does addition of an EWG to amide reduce the self destruction mechanism of penicillin?

Answer 17

Reduced amide O tendency to act as a nucleophile;

More stable
Survives stomach acid - oral admin.
Still sensitive to ß-lactamases though

Question 18

How can penicillin be made resistant to ß-lactam cleavage by ß-lactamases?

Answer 18

By introducing a steric blockade, bulky and EWG R group added to amide side chain;

Means greater acid stability and resists cleavage by ß-lactamases