Synthesis of drugs: lead optimisation

Question 1

What are the five strategies to alter the lead?

Answer 1

Vary alkyl substituents 
Extension - extra functional group
Isosteres
Simplification
Rigidification

Question 2

Alkyl groups are lipophilic. They may interact with the _________ region in the binding site

Answer 2

hydrophobic

Question 3

Varying the ________ and _________ of the group optimises interaction with receptor and introduces selectivity.

Answer 3

length

bulk

Question 4

What is the rationale for extension (extra functional group)?

Answer 4

explore target binding site for further binding regions to achieve additional binding interactions

Question 5

Antagonists can be made from antagonists by which form of leading optimisation?

Answer 5

extension

Question 6

Adding an extra functional group to adrenaline leads to it becoming the B-blocker _________

Answer 6

propranolol

Question 7

What is the rationale for isosteres?

Answer 7

leads to more controlled changes in steric/electronic properties.
May affect binding and/or stability
(substitute an atom - molecules remains similar size)

Question 8

Isosteres are useful for structure activity relationships. True or false?

Answer 8

True

Question 9

In propranolol (B-blocker), replacing OCH2 with NHCH2 retains activity. Whereas replacing OCH2 with CH=CH, CH2CH2, SCH2 eliminates activity. What does this imply?

Answer 9

That oxygen is involved in binding (H bond acceptor)

Question 10

What is the rationale for simplification?

Answer 10

Lead compounds from natural sources are often complex and difficult to synthesise - simplifying the molecule makes the synthesis of analogues easier, quicker and cheaper.
Simpler structures may fit the binding site easier and increase activity
Simpler structures may be less toxic if excess functional groups are removed

Question 11

What are the two methods of simplification?

Answer 11

Retain the pharmacophore and remove unnecessary functional groups
Remove excess rings

Question 12

What are the disadvantages of simplification?

Answer 12

Oversimplification may result in decreased activity and selectivity
Simpler molecules have more conformations
More likely to interact with more than one binding site (i.e. decrease selectivity)
May result in increased side effects

Question 13

What is the rationale for rigidification?

Answer 13

lead compounds are often simple, flexible and fit several targets due to different active conformations. The strategy is to rigidify the molecule to limit conformations. It will increase activity - more chance of desired active conformation active conformation being present.
It will increase selectivity - less chance of undesired active conformations

Question 14

What is the disadvantage of rigidification?

Answer 14

molecule is more complex and may be more difficult to synthesise

Question 15

What are the two methods of rigidification?

Answer 15

Introduce rings - bonds are locked within the ring structure and cannot rotate freely
Introduce rigid functional groups

Question 16

Adding a steric conformational blocker e.g. CH3 to serotonin antagonist leads to an increase in activity and the active conformation is retained. This is an example of which type of lead optimisation?

Answer 16

Rigidification