1. ANTIULCER AGENTS Patrick An Introduction to Medicinal Chemistry 3/e
Chapter 22
ANTIULCER AGENTS
Part 3: Proton pump inhibitors

2. Contents
Part 3: Proton pump inhibitors
23. Parietal Cells and the Proton Pump
24. Proton Pump Inhibitors
25. Mechanism of inhibition
26. Design of omeprazole (Losec)
26.1. The lead compound
26.2. Modification of the thiourea group
26.3. Modify the imidazole ring
26.4. Drug metabolism studies
26.5. Add substituents to the heterocyclic rings
26.6. Substituents varied on the pyridine ring
26.7. Substituents varied on the benzimidazole ring
27. Esomeprazole (Nexium)
28. Synthesis of Omeprazole
[11 slides]

3. 23. Parietal Cells and the Proton Pump
Lumen of the stomach
Proton pump
Receptors
Ion channels
Cck2 H2 M3
ATP
ADP + Pi H + + K
HCl Cl -
Canaliculus
The proton pump
Pumps protons out of the parietal cell and potassium ions back in
Requires energy - provided by hydrolysis of ATP to ADP, catalysed by ATPase
The proton pump is also called H+/K+-ATPase
Chloride ions depart through a separate ion channel
HCl is formed in the canaliculus
The potassium ions exit the parietal cell as counterions for the chloride ions and are then pumped back in
A separate potassium ion channel is used for K+ ions leaving the cell

4. 24. Proton Pump Inhibitors
Act as prodrugs
Activated by strongly acidic conditions found in the canaliculae of parietal cells

5. 25. Mechanism of inhibition

6. 26. Design of omeprazole (Losec)
26.1. The lead compound
Originally an antiviral drug
Inhibits gastric acid secretion
Liver toxicity due to the thioamide group
26.2. Modification of the thiourea group
Inhibits gastric acid secretion
The pyridine ring and bridging CH2S moiety are important to activity

7. 26. Design of omeprazole (Losec)
26.3 Modify the imidazole ring
Increase in activity due to the benzimidazole ring
26.4 Drug metabolism studies
Timoprazole formed by metabolism of H124/26
Timoprazole is the active drug
Pyridinylmethylsulfinyl benzimidazole structure
Side effect - inhibits iodine uptake by the thyroid gland

8. 26. Design of omeprazole (Losec)
26.5 Add substituents to the heterocyclic rings
Potent antisecretory properties over long periods of time
No toxic side effects on the thyroid
No other serous side effects

9. 26. Design of omeprazole (Losec)
26.6 Substituents varied on the pyridine ring
Substituents which increase the basicity of the pyridine ring are good for activity
Promotes the mechanism of activation
Methyl substituents at the meta position have an inductive effect
Methoxy substituent are more effective at para position than meta position
Resonance effect increases electron density on the nitrogen
H159/69 is potent but chemically too labile

10. 26. Design of omeprazole (Losec)
26.7 Substituents varied on the benzimidazole ring
Substituents were varied to get the right balance of potency, chemical stability and synthetic accessibility
Omeprazole was found to have the best balance
Launched in 1988 by Astra
World’s biggest selling drug

11. 27. Esomeprazole (Nexium)
Omeprazole has an asymmetric centre
The S-enantiomer has better potency and pharmacokinetic profile
Example of chiral switching

12. 28. Synthesis of Omeprazole