ACE inhibitor development

Question 1

what is a structure activity relationship

Answer 1

the relationship between chemical structure and pharmacological activity for a series of compounds

Question 2

what is the aim of a structure activity relationship

Answer 2

identify which functional groups are important for binding/activity

Question 3

what is the method of a structure activity relationship

Answer 3

1. alter, remove or mask a functional group
2. test the analogue for activity
3. conclusions depend on the method of testing
   - in vitro- tests for binding interactions with target
   - in vivo- tests for target binding interactions/pharmacokinetics
   - if in vitro activity drops, it implies group is important for binding
   - if in vivo activity is unaffected, it implies group is not important

Question 4

what are quantitive structure activity relationships

Answer 4

mathematical relationships linking chemical structure and pharmacological activity in a quantitive manner for a series of compounds

Question 5

what is a pharmacophore

Answer 5

structure that effectively binds to the specific therapeutic target to produce the desired effect by triggering or blocking its biological response
- serves as a template for the synthesis of analogues during optimisation

Question 6

what is teprotide

Answer 6

a peptide from bothrops venom

- a potent, selective ACE inhibitor

Question 7

what substrates for ACE are required by iteration

Answer 7

• a free carboxyl group on the C terminal
• that proline is not present in the penultimate- position to the C terminal
• a hydrophobic amino acid is present at the ante-penultimate position to the c terminal

Question 8

describe the structure of teprotide

Answer 8

• has a free -COOH on C terminal
• pro is present in penultimate position
• hydrophobic aa (isoleucine) is present in ante-penultimate position
• is not a substrate ACE, it is an inhibitor

Question 9

give examples of side effects of captopril (ACE inhibitor)

Answer 9

rash, loss of taste, metallic taste in mouth

Question 10

why was a methyl group introduced in the development of carboxylate containing ACE inhibitors

Answer 10

methyl group introduced to counterbalance hydrophilicity of introduced nitrogen

Question 11

define prodrug

Answer 11

a class of drugs, the pharmacologic action of which results from conversion by metabolic processes within the body (biotransformation)