Synthetic drugs

Question 1

What is the process of leading a drug from discovery to market (7)

Answer 1

1. Target identification
2. Hit identification
3. Hit-to-lead
4. Lead optimisation
5. Preclinical development
6. Clinical trials (phases I to iii)
7. Marketing authorisation

Question 2

What are the sources of drug molecules (4)

Answer 2

1. Chemicals
2. Herbs
3. DNA
4. HIT

Question 3

What are synthetic drugs (3)

Answer 3

1. Drugs obtained by synthesis and semi-synthesis
2. synthesis (e.g. hydralazine)
3. semi-synthesis (e.g. cephalosporin C produced by fungi, Cetizoxime)

Question 4

How do we know what molecule to make (synthetic drugs) (8)

Answer 4

1. Target identification
2. Hit identification
3. Random screening
4. ‘’me too’’ approach
5. Metabolite studies
6. Selective optimisation of side effects
7. Database mining
8. Rational drug design

Question 5

What is random screening (5)

Answer 5

1. When any new species (synthetic or natural) was tested against all biological tests available
2. Benefit = Does not require knowledge of
   the target system
3. Con = Intrinsically “random”
4. Con Costs money or needs luck.
5. This approach evolved into High-Throughput Screening.

Question 6

What is ‘’me-too’’ aka ‘’follow on’’ (5)

Answer 6

1. Drug development approach based on either
2. Hitting the same target system as someone else
3. Optimising the efficacy of a marketed or known drug
4. Benefit = Provide more therapeutic options
   Improve the efficacy (me better)
5. Con = Reduce incentives for innovation
   Wasteful if too similar to “inspiration”

Question 7

What are metabolite studies (4)

Answer 7

1. When metabolites of known drug molecules (on the market or candidates) are screened for activity against the same or a broader target system

This results in:

1. Better pharmacokinetic (longer
   duration, better absorption…)
2. Less toxic
3. Fewer side effects

Question 8

What is selective optimisation of side effects (2)

Answer 8

1. The observation of a side effect of a particular drug leads to find
   structural features responsible for that effect
2. A drug can bind to the receptor responsible for the desired effect and the receptors responsible for side effects.

Question 9

What is database mining (2)

Answer 9

1. When the target is known, a semi-rational approach can be adopted.
   A “preferred motif” can be sourced from available molecule databases.
2. Structures are selected on the
   basis of molecular features
   (dipoles, π-areas, acidic/basic,
   steric features, etc…)

Question 10

What is the rational design (4)

Answer 10

1. When the target is known and/or the endogenous ligand is known,
   a molecule can be specifically tailored.
2. known target (protein, enzyme,
   receptor, etc.)
3. known ligand (receptor agonist/antagonist,
   enzyme substrate)
4. drug is designed to match the feature of the ligand or the target

Question 11

How is rational design used to mimic the ligand (2)

Answer 11

1. The drug can be modelled on the ligand molecule if a physio-pathological hypothesis is available.
2. e.g. gastric acid secretion is stimulated by histamine → guanylhistamine (weak antagonist to H2 receptors) → cimetidine (marketed antiulcer)

Question 12

How is the rational design used to match the target (4)

Answer 12

1. The physio-pathological hypothesis must be available.
2. The model of the target must be known.
3. It is virtually impossible if not computer-aided
4. HIV-1 protease inhibitor (Saquinavir) is an example of a drug designed with this method

Question 13

What is the process of drug synthesis (5)

Answer 13

1. Idea
2. Hit identification, lead identification, lead optimisation - discovery.
3. Toxicology batches, phase 1 - chemical process research
4. Phase 2, phase 3 - chemical process development
5. Market

Question 14

What are the implications of scale-up (3)

Answer 14

1. More than getting hold of larger crockery
2. Scaling up makes all operations more labour-demanding
3. Factors overlooked at the discovery stage can become reasons for synthesis failure.

Question 15

What must be considered from discovery to manufacture (6)

Answer 15

1. Once the drug candidate is identified, chemical process research and development should be parallel to drug development.
2. Reagents (cost, availability, purity, toxicity)
3. Solvents (as above + easy to be removed)
4. Number of steps (less steps means less handling, hence less cost)
5. The ruggedness of the reaction (exothermic requires special equipment?)
6. Isolation and purification of product (crystallisation preferred)

Question 16

What causes impurities in the synthetic process (5)

Answer 16

1. Impurity = any chemical species different from the desired product
2. Product of side reaction
3. Reagent residues if the reaction is incomplete
4. Residues of catalysts
5. Impurity can cause toxicity!