6B. 9/3/26 - NSAIDs: Salicylates, Fenamates, Oxicams & COX-2 Inhibitors

What are  Oxicams?

Piroxicam + meloxicam

Oxicams: core structure

Piroxicam + meloxicam

• Acidic group = enol, NOT carboxylic acid; Enol donates H⁺ → negatively charged form; Negative charge is stabilized by an intramolecular interaction

• Anion binds arginine in the COX active site

• Both have 2 conjugated aromatic groups → stronger potency

• Fused rings count as one aromatic group.

Oxicams: core structure

Recognizing them

• Piroxicam →

• Meloxicam →

• Piroxicam → pyridine ring → think P = pyridine

  • a 6-membered ring

  • 5 carbons + 1 nitrogen

• Meloxicam → methylthiazole ring

  • a 5-membered ring

  • containing sulfur (S) and nitrogen (N)

  • with a methyl group (–CH₃) attached to it

Piroxicam

Meloxicam

Piroxicam vs meloxicam

chart

	Piroxicam	Meloxicam
COX preference	COX-1	COX-2
GI risk	Higher	Lower
Half-life	~50 hr	~20 hr
Metabolizing CYP	CYP2C9	CYP2C9
Phase I	Aromatic hydroxylation	Benzylic hydroxylation
Phase II	Glucuronide ether (glucuronic acid attaches to an –OH group)	Glucuronide ester (glucuronic acid attaches to a carboxylic acid –COOH)

Piroxicam → ___ COX-1 inhibition in gut →

Meloxicam → ____ COX-1 inhibition in gut →

Piroxicam → more COX-1 inhibition in gut → greater GI toxicity

Meloxicam → less COX-1 inhibition in gut → lower GI toxicity.

What type of Nsaids are Piroxicam vs Meloxicam?

Both are still nonselective NSAIDs; they simply have a preference.

Meloxicam concern?

Greater COX-2 preference → somewhat greater cardiovascular concern.

Piroxicam Metabolism

CYP2C9

→ aromatic hydroxylation at para position on ring 2

→ aromatic OH

→ glucuronidation

→ glucuronide ETHER

Meloxicam Metabolism

CYP2C9

→ benzylic hydroxylation

→ primary alcohol

→ aldehyde

→ carboxylic acid

→ glucuronidation

→ glucuronide ESTER.

Piroxicam vs meloxicam

Metabolic-speed theme

• Aromatic hydroxylation = slower

• Benzylic oxidation = faster

• Professor connected this with piroxicam's longer half-life, while also noting tissue distribution

COX-2 selective drugs

Major structural clue:

3 independent aromatic rings

→ bulky structure
→ does not fit COX-1 appropriately
→ can access COX-2.

What’s the marketed COX-2-selective drug?

Celecoxib

Why celecoxib is COX-2 selective?

Valine gatekeeper residues = smaller

→ allosteric site accessible

→ celecoxib fits.

COX-1

Isoleucine gatekeepers = larger

→ block allosteric site

• active site itself too small for celecoxib.

Therefore:

Celecoxib → COX-2 allosteric site.

What is Celecoxib acidic group?

sulfonamide → ionizes → interacts with arginine in the allosteric region.

Celecoxib metabolism

Celecoxib

→ CYP2C9

→ benzylic oxidation

→ primary alcohol

→ aldehyde

→ carboxylic acid

→ glucuronidation

→ excretion.

TXA₂ vs PGI₂

	Action
TXA₂	Vasoconstriction + platelet aggregation ↑
PGI₂	Vasorelaxation + platelet aggregation ↓

Why celecoxib has CV concern?

Celecoxib inhibits COX-2

→ PGI₂ ↓

→ TXA₂ : PGI₂ balance shifts toward TXA₂

→ vasoconstriction + platelet aggregation ↑

→ cardiovascular risk concern.