Week 12 - Medicinal Chemistry of Cyclooxygenase (COX) Inhibitors

Question 1

What role COX play in prostaglandin synthesis

Answer 1

Inihibt cycloocygenase (COX1/2) will ionhibit conversion of AA into prostaglandins

Pocess of prostaglandin synthesis: cyclooxyganse (COX do)
1. Have arachadonic acid (AA)
2. Cyclooxyganse (COX-1 and COX-2) introduce 2 oxygen atoms (~oxygenase) to AA
3. Leads to formation of an intermediate
4. Peroxidase acts on intermediate leading to formation of prostaglandin

Question 2

What are the issues related to inhibiting COX-1 and COX-2

Answer 2

Inhibition of COX-1:
- cause GI issues e.g. stomach irritation
- GI issues is a common problem for patients using NSAIDs

Inhibition of COX-2:
- cause CV issues BUT no stomach issues
- can cause blood clots, etc.

Need to design NSAID that has a balance of inihibtion
- if inhibits one COX enzyme more it will increase the risk of either GI or CV issues
- e.g. ibuprofen is a balance of inhibition

Question 3

What are similar feature “-fen” NSAIDs have

e.g. ibuprofen, naproxen etc.

Answer 3

• carboxylic acid group (at physiological pH will be in anionic form when past stomach)
• can interact with hydrogen bond donors, N, O and H
• stereogenic centre / chiral centre
• all have methyl group (a small hydrophobic group)
• aromatic (ring) side chains

Shared features are required for drug to exert action

Question 4

What is aceclofenac a prodrug for and how

Answer 4

Aceclofenac is a pro-drug for diclofenac (improves absorption, or another PK parameter)

ACECLOFENAC is likely to be chemically unstable due to ester group
- when ester is hydrolysed molecule turns into diclofenac

Question 5

KEY INFO

Answer 5

• The lower the conc. it takes to exert effect = the more potent the drug is