Med Chem

Question 1

List the 3 broad approaches to structural modification for lead optimization.

Answer 1

1) Analoguing
2) Simplification (disjunctive approach)
3) Adding groups (conjunctive approach)

Question 2

Describe analoguing and its purpose.

Answer 2

• Explore SAR through specific changes to determine the importance of specific functional groups in target binding/interaction
• Results in the development of broadly similar compounds to the lead, sometimes with conferred greater benefits

Question 3

Describe simplification and its purpose.

Answer 3

• Removal of unnecessary groups from the lead (usually for natural compounds)
• Create simpler compounds which are easier and more practical to synthesize, while retaining key interactions.

Question 4

Describe addition of groups and its purpose.

Answer 4

• Addition of entirely extra functional groups, particularly in leads that are small
• Create/probes for new interactions, to increase binding affinity and pharmacological effect
• May also result in changes in MW and cLogP, which alters the absorption and permeability of the drug

Question 5

List the structural modification strategies. (9)

Answer 5

1) Variation of substituents
2) Chain extension/contraction
3) Ring expansion/contraction
4) Ring variation
5) Ring fusion
6) Extension of structure
7) Isosteric replacement
8) Simplification of structure
9) Stereoisomers