L2 - PK in Drug Synthesis Soft Drug Design

Question 1

Prodrugs - 2

Answer 1

1. Prodrugs (compounds inactive until activated by metabolism) e.g. heroin, clopidogrel
2. Pro-drug design can help improve bioavailability, prolong duration of action, increase the available routes of administration

These structures recommended to understand mechanism of ester hydrolysis.
e.g. Bambuterol’s ester is hydrolysed producing a phenol & a –COOH

Question 2

Soft drugs - 3

Answer 2

1. Soft drugs (active, then deactivated by metabolism)
2. The route of deactivation is built into the drug.
3. Produces inactive, non-toxic metabolites

Question 2

Why use Soft drugs – 3

Answer 2

1. To reduce duration of action
2. To reduce S/Es by limiting drug distribution
3. Predictable metabolism to inactivate drug reduces risk of metabolism creating multiple metabolites with varying biological activities

Question 3

Soft drugs: Design - 5

Answer 3

1. can’t modify API too much, or risk altering pharmacological activity
2. Intro of metabolically sensitive group shouldn’t change physical, steric & electronic properties of the lead
3. Ideally metabolizable isostere (functional groups with similar electronic & steric properties resulting in similar biological activity)
4. Most common: ester, carbamates & quaternary nitrogen
5. Addition of these functional groups will reduce the drug’s duration of action

Question 4

Adaprolol – 2

Answer 4

1. Sufficiently long acting to reduce intraocular pressure
2. Rapidly hydrolysed in systemic circulation & so has minimal undesired cardiovascular/pulmonary activity