NSAIDs and cyclooxygenase template

Aspirin, ibuprofen, naproxen, diclofenac and celecoxib with the acidic group (or celecoxib’s sulfonamide) circled, notes on how each binds COX-1 and COX-2, and aspirin’s irreversible acetylation of Ser530.

What the template shows

• Carboxylic acids that block the COX channel, and the sulfonamide that makes celecoxib COX-2 selective
• Five NSAIDs
• carboxylic acid (binds Arg120)
• aspirin acetyl / celecoxib SO₂NH₂
• acetylates Ser530: irreversible (COX-1 > COX-2); pKa 3.5
• 2-arylpropionic acid (racemate; S is active, R inverts in vivo)
• (S)-2-arylpropionic acid, sold as one enantiomer
• arylacetic acid; 2,6-Cl₂ twists the rings apart
• COX-2 selective: no acid; SO₂NH₂ fills the COX-2 side pocket
• COX-1 and COX-2 turn arachidonic acid into PGH₂, the precursor of prostaglandins and thromboxane: block them and pain, fever and inflammation fall.
• Classical NSAIDs are acids (pKa 3.5–4.5): the carboxylate pairs with Arg120 at the mouth of the channel and the aryl part blocks it. Ionised acids also concentrate in the stomach wall, adding to GI damage.
• Aspirin transfers its acetyl group to Ser530: COX is blocked for the life of the enzyme, and platelets (no nucleus) cannot make more, hence low-dose aspirin as an antiplatelet drug.
• COX-2 has Val523 where COX-1 has Ile523, opening a side pocket; the SO₂NH₂ of celecoxib binds there (with Arg513), giving COX-2 selectivity and less gastric harm.
• Ibuprofen and naproxen are 2-arylpropionic acids (“profens”); the (S)-enantiomer inhibits COX.
• Patrick, An Introduction to Medicinal Chemistry · every part of this sheet is editable

Drawn with 90 atoms, 23 shapes – every one editable in MolDraw.

Sources

• Patrick, An Introduction to Medicinal Chemistry, 6th ed., OUP 2017 Textbook