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

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]

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

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

25. Mechanism of inhibition

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

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

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

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

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

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

28. Synthesis of Omeprazole