Methods of Drug Discovery - Anti-inflammatory drugs (4)

Question 1

Long-term anti-inflammatory drugs

Answer 1

Swells up intestines or gastric tract – bleeding

Question 2

3 types of AN drugs; what kind of mixture

Answer 2

Ibuprofen, Ketoprofen and Naproxen; Racemic

Question 3

How to keep stomach acid under control?

Answer 3

Add proton pump inhibitor so that naproxen can be released and bring inflammation back down

Question 4

What are NASID’s?

Answer 4

• Drugs that relieve pain, fever, inflammation … not cardio protective
• Non-steroidal AN drugs

Question 5

What do the Cox-1 and Cox-2 have in common? Not in common?

Answer 5

• Both inhibit prostaglandins formation (Hormone that causes inflammation) with the help of a painkiller
• However, cox-1 mediates the renewal of stomach acid - gastric bleeding

Question 6

What to do about Cox 1 or 2? How? (1st step)

Answer 6

• Selective inhibiter for Cox-2 and in turn leave Cox-1 alone
• Develop Bio-assay… see selectivity of known drugs for each Cox enzymes

Question 7

Where are the 2 Cox’s found?

Answer 7

Cox-2: Macrophages

Cox-1: Kidney

Question 8

Dupont Structure

Answer 8

Potent inflammatory activity but no gastric side effects - Had to optimize the structure

Question 9

Merck and pfizer were racing to find out which sites of enzyme could tolerate modifications… What are the variations???

Answer 9

I. A central 5 membered ring (heterocyclic in nature)
♣ Likely aromatic
II. 2 aromatic rings are “ortho” to each other
♣ probably contains benzene rings (aromatic) but may be 5-membered
III. Substituents on 2 phenyl rings
IV. Substituents on the central 5 membered ring

Question 10

Vioxx and Celebrex… key app?

Answer 10

• Long term arthritis

- Sports injuries

Question 11

What was the problem with vioxx?

Answer 11

• Long term use of vioxx contributed in increased risks of heart attacks or stoke (found in the research for colon cancer)
• Concerns for cox-2 inhibitors and long term use of NASID’s arised

Question 12

Re-introduction of Vioxx?

Answer 12

• Health Canada/FDA recommended that vioxx should be marketed again as cardiovascular risks were no different from Ibuprofen’s.
• They also recommended further studies
• Merck has never brought it back to market.. not worth the risk?
• Pfizer just stopped advertising Celebrex but it was still sold… resumed again few years lata

Question 13

Vioxx as a cox-2 inhibitor?

Answer 13

Much better than Celebrex… However, it did more than reduce inflammation
- Celebrex does not interfere with the pathway as much as Vioxx

Question 14

What does Cox-2 do then…?

Answer 14

• Cardio protection
• Involved in production of prostacyclin (platelet vasodilator) + inhibits platelet aggregations
• releases prostaglandins – promotes inflammation

Question 15

How to optimize structure?

Answer 15

• need structural requirements of the dupont drugs
  1. 5 membered ring - aromatic
  2. 2 aromatic rings that are ortho to each other
  3. substituents on phenyl group
  4. substituents on 5 membered ring