W3 L2 - Medicinal chemistry on omeprazole & PPIs

Question 1

Structure-Activity Relationship (SAR) meaning

Answer 1

• Drug properties (dissolution, absorption, metabolism, etc.) are governed by molecular structure
• SAR is developed through: Design-make-Test-Analyse cycle.

Question 2

early drug development: drugs in order

Answer 2

H1 histamine antagonists, H2 receptors, cimetidine, ranitidine

Question 3

Peptic Ulcer Disease & Early Drug Development

Answer 3

• Cause: Aggravated by excessive HCl secretion in stomach.
• Early treatments: H1 histamine antagonists (e.g., chlorphenamine) had no gastric benefit.
• histamine involved in gastric acid release
• Discovery: H2 receptors mediate gastric acid secretion.
• Cimetidine (1976): First effective H2 antagonist but short-acting (4–8 hrs).
• Ranitidine: Improved potency and duration (taken 2× daily).

Question 4

omeprazole development: drugs in order

Answer 4

CM-131, sulfoxide analogues, picoprazole, omeprazole

Question 5

Birth of Omeprazole

Answer 5

• Early compound CMN-131: Active but toxic.
• Optimization led to: Sulfoxide analogues with increased activity but stability/toxicity issues.
• Picoprazole: Good efficacy, poor aqueous stability.
• Final optimization: Adjusted electron density on pyridine & benzimidazole to balance potency and stability.
• Omeprazole: Developed as a prodrug, activated in acidic pH (gastric lumen) → forms active sulfenamide.

Question 6

Mechanism of Action of omeprazole

Answer 6

• Target: H⁺/K⁺-ATPase on gastric parietal cells.
• Uses ATP to pump H⁺ ions → stomach lumen.
• Action: Omeprazole irreversibly binds to Cys813 of the proton pump.
• Result: Inhibits acid secretion → increases gastric pH.

Question 7

Pharmacodynamics of omeprazole: prodrug, inhibition, mechanistic basis of potency

Answer 7

• Prodrug: Activation occurs in acidic stomach environment.
• Irreversible inhibition: Long-lasting effect even after plasma drug is cleared.
• Mechanistic basis of potency:
• Ki : Reversible binding affinity.
  Kintact: Rate of irreversible reaction (dominates for omeprazole).

Question 8

Pharmacokinetics (systemic action)
Formulation and stability

Answer 8

• Systemic action: Despite acting in stomach, omeprazole is absorbed and delivered via systemic circulation.
• Formulation challenge: Requires enteric coating to prevent degradation in stomach acid before absorption.
• Stability: Influenced by pH and structure (balance between potency & acid stability).

Question 9

Stereochemistry – Omeprazole vs. Esomeprazole

Answer 9

• Omeprazole: Racemic mixture (R- & S-enantiomers).
• Esomeprazole (S-enantiomer):
• Slower metabolism than R-form.
• Higher systemic exposure and reduced clearance.
• Approved as a distinct, more effective drug (2001).

Question 10

Clinical Relevance

Answer 10

• Omeprazole & PPIs: Revolutionized treatment for acid-related disorders (ulcers, GERD).
• Structure and chemistry crucial to optimizing stability, potency, and pharmacokinetics.