PROTON PUMP INHIBITORS
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The document discusses proton pump inhibitors (PPIs), focusing on their mechanism of action, specifically the proton pump located in parietal cells. It details the drug design and structure of omeprazole, its modifications, and also highlights the advantages of its s-enantiomer, esomeprazole. Additionally, the document covers the synthesis process of omeprazole and its significance in inhibiting gastric acid secretion.
PROTON PUMP INHIBITORS
- 1. PROTON PUMP INHIBITORS Md. Saiful Islam B.Pharm, M.Pharm (PCP) North South University Join Facebook : Pharmacy Universe
- 2. Lumen of the stomach Proton pump Receptors Ion channels Cck2 H2 M3 ATP ADP + Pi 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 1. Parietal Cells and the Proton Pump H+ +K HCl Cl -
- 3. 2. Proton Pump Inhibitors py r i di ne m e t hy l s ul f i ny l ' l i nke r ' be nz a m i da z o l e Notes •Act as prodrugs •Activated by the strongly acidic conditions found in the canaliculae of parietal cells Pantoprazole H N N OCHF2 S O N OMeMeO Rabeprazole Na N N S O N MeO MeO Lansoprazole H N N S O N MeO F3C Omeprazole H N N OMe S O N MeMeO Me
- 4. •Originally an antiviral drug •Inhibits gastric acid secretion •Liver toxicity due to the thioamide group 4. Design of omeprazole (Losec) 4.1. The lead compound 4.2. Modification of the thiourea group •Inhibits gastric acid secretion •The pyridine ring and bridging CH2S moiety are important to activity N NH2 S CMN 131 N S N H N H 77/67
- 5. Increase in activity due to the benzimidazole ring 4.3 Modify the imidazole ring 4.4 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 4. Design of omeprazole (Losec) N S N H N H 124/26 benzimidazole pyridine N S N H NO Timoprazole
- 6. •Potent antisecretory properties over long periods of time •No toxic side effects on the thyroid •No other serious side effects 4.5 Add substituents to the heterocyclic rings 4. Design of omeprazole (Losec) N S N H NO Picoprazole CO2Me Me Me
- 7. 4.6 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 is more effective at para position than meta position •Resonance effect increases electron density on the nitrogen •H159/69 is potent but chemically too labile 4. Design of omeprazole (Losec) N S N H NO CO2Me Me MeMeO Me H 159/69 N MeMeO Me R N MeMeO Me R N MeMeO Me R N MeMeO Me R
- 8. 4.7 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 4. Design of omeprazole (Losec) Omeprazole H N N OMe S O N MeMeO Me
- 9. 5. Esomeprazole (Nexium) •Omeprazole has an asymmetric centre •The S-enantiomer has better potency and pharmacokinetic profile •Example of chiral switching H N N OMe SN MeMeO Me O
- 10. N Cl Pyridine portion Me OMe Me alkyl chloride 6. Synthesis of Omeprazole N N H HS OMe Benzimidazole portion thiol + N N H S OMe N Me Me MeO NaOH N N H S OMe N Me Me MeO Omeprazole O O2H O Cl meta-chloroperbenzoic acid