SAR

Question 1

What’s a lead compound

Answer 1

Prototype chemical structure with desired biological activity

Question 2

Stages of drug development

Answer 2

Choose target 
Validate biology 
Lead discovery 
Refinement SAR
Final optimisation 
Market

Question 3

What is SAR

Answer 3

Structure activity relationship - synthesis a range of compounds that are related to lead compound to decide which functional group is important for what biological activity

Question 4

Strategy for converting agonist to antagonist

Answer 4

Add extra functional group to find extra binding intertractions
Block receptor activation

Question 5

The change in design of compound (based on histamine lead) over time

Answer 5

1) add hydrophobic group to histamine –no effect
2) N alpha- guanylhistamine. add hydrophilic group: guanidine- PARTIAL agonist, prevents histamine from fully promoting the release of HCL
3) chain extension- push polar region FURTHER out to interact with antagonist binding region
4) burimamide. thiourea group- no Ag. Activity weak ANTag, toxic E
5) cimetidine. Cyanoguaidine moiety

Question 6

Three binding regions of N guanylhistamine

Answer 6

1) imidazole ring (heterocyclic ring)
2) 2 polar binding regions (guanidine)
One accessed by agonist (NH)
The other by antagonist (2 NH2)

Question 7

How is it a partial agonist?

Answer 7

The polar region (+ve) is more diffuse and FURTHER OUT than in histamine, allows it to bind receptor in 2 different modes

The antagonist polar region is further from the imidazole binding region

Question 8

Explain what is bioisosteric replacement of thiourea to cyanoguanidine

Answer 8

Chemical substitutes with similar physical and chemical properties (both trigonal planar, polar but neutral, hydrophilic)
Produce similar biology activity

Question 9

What is the principle of QSAR

Answer 9

Identify and quantify the physiochemical properties of drug (as a whole or specific group) and investigate if they affect its biological activity.
Hydrophobicity, electronic effects

Question 10

What is the outrider from the logP of cimetidine analogues vs. Activity graph? And why
What drug contains this group?

Answer 10

Nitroketeneanimal
More active than it should be based on the low logP
Ranitidine