patrick an introduction to medicinal chemistry 3/e chapter 22 antiulcer agents
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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) - PowerPoint PPT PresentationTRANSCRIPT
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Patrick Patrick An Introduction to Medicinal An Introduction to Medicinal
ChemistryChemistry 3/e 3/e
Chapter 22Chapter 22
ANTIULCER AGENTSANTIULCER AGENTS
Part 3: Proton pump inhibitorsPart 3: Proton pump inhibitors
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ContentsContents
Part 3: Proton pump inhibitors
23. Parietal Cells and the Proton Pump24. Proton Pump Inhibitors25. Mechanism of inhibition26. Design of omeprazole (Losec)
26.1. The lead compound26.2. Modification of the thiourea group26.3. Modify the imidazole ring26.4. Drug metabolism studies26.5. Add substituents to the heterocyclic rings26.6. Substituents varied on the pyridine ring26.7. Substituents varied on the benzimidazole ring
27. Esomeprazole (Nexium)28. Synthesis of Omeprazole
[11 slides]
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Lumen of the stomach
Proton pump
Receptors
Ion channels
Cck2H2
M3
ATP ADP + Pi
Canaliculus
The proton pumpThe proton pump • Pumps protons out of the parietal cell and potassium ions back inPumps protons out of the parietal cell and potassium ions back in• Requires energy - provided by hydrolysis of ATP to ADP, catalysed by Requires energy - provided by hydrolysis of ATP to ADP, catalysed by
ATPaseATPase• The proton pump is also called HThe proton pump is also called H++/K/K++-ATPase-ATPase• Chloride ions depart through a separate ion channelChloride ions depart through a separate ion channel• HCl is formed in the canaliculusHCl is formed in the canaliculus• The potassium ions exit the parietal cell as counterions for the chloride ions The potassium ions exit the parietal cell as counterions for the chloride ions
and are then pumped back inand are then pumped back in• A separate potassium ion channel is used for KA separate potassium ion channel is used for K++ ions leaving the cell ions leaving the cell
23. Parietal Cells and the Proton Pump23. Parietal Cells and the Proton Pump
H+ +K
HCl
Cl-
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24. Proton Pump Inhibitors24. Proton Pump Inhibitors
Pantoprazole
HN
N
OCHF2
S
O
N
OMeMeO
pyridine
methylsulfinyl'linker' benzamidazole
Omeprazole
HN
N
OMe
S
O
N
MeMeO
Me
Lansoprazole
HN
N
S
O
N
MeO
F3CRabeprazole
NaN
N
S
O
N
MeO
MeO
• Act as prodrugsAct as prodrugs• Activated by strongly acidic conditions found in the canaliculae Activated by strongly acidic conditions found in the canaliculae
of parietal cellsof parietal cells
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25. Mechanism of inhibition25. Mechanism of inhibition
HN
N OMe
SO
N
Me
OMe
Me
H
H+
N
N OMe
SO
N
Me
OMe
Me
H
H NH
N
OMe
H
N
S
O
Me Me
OMe
Spiro intermediate
H
-H+
N
N
OMe
N
S OH
MeMeO
Me
H
Sulfenic acid intermediate
-H2O
N
MeMeO
Me
S
N
N
OMe
Pyridinium sulfenamide structure
HS Protonpump
H
N
MeMeO
Me
NH
N
OMe
S SProtonpump
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• Originally an antiviral drugOriginally an antiviral drug• Inhibits gastric acid secretionInhibits gastric acid secretion• Liver toxicity due to the thioamide groupLiver toxicity due to the thioamide group
26. Design of omeprazole (Losec)26. Design of omeprazole (Losec)
26.1. The lead compound26.1. The lead compound
N
NH2
S
CMN 131
26.2. Modification of the thiourea group26.2. Modification of the thiourea group
N S
NH
N
H 77/67
• Inhibits gastric acid secretionInhibits gastric acid secretion• The pyridine ring and bridging CHThe pyridine ring and bridging CH22S moiety are important to activityS moiety are important to activity
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• Increase in activity due to the benzimidazole ringIncrease in activity due to the benzimidazole ring
26.3 Modify the imidazole ring26.3 Modify the imidazole ring
26.4 Drug metabolism studies26.4 Drug metabolism studies
• Timoprazole formed by metabolism of H124/26Timoprazole formed by metabolism of H124/26• Timoprazole is the active drugTimoprazole is the active drug• Pyridinylmethylsulfinyl benzimidazole structurePyridinylmethylsulfinyl benzimidazole structure• Side effect - inhibits iodine uptake by the thyroid glandSide effect - inhibits iodine uptake by the thyroid gland
N S
NH
N
H 124/26
benzimidazole
pyridine
N S
NH
NO
Timoprazole
26. Design of omeprazole (Losec)26. Design of omeprazole (Losec)
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• Potent antisecretory properties over long periods of timePotent antisecretory properties over long periods of time• No toxic side effects on the thyroidNo toxic side effects on the thyroid• No other serous side effectsNo other serous side effects
26.5 Add substituents to the heterocyclic rings26.5 Add substituents to the heterocyclic rings
N S
NH
NO
Picoprazole
CO2Me
Me
Me
26. Design of omeprazole (Losec)26. Design of omeprazole (Losec)
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26.6 Substituents varied on the pyridine ring26.6 Substituents varied on the pyridine ring
• Substituents which increase the basicity of the pyridine ring are good for Substituents which increase the basicity of the pyridine ring are good for activityactivity
• Promotes the mechanism of activationPromotes the mechanism of activation• Methyl substituents at the Methyl substituents at the metameta position have an inductive effect position have an inductive effect• Methoxy substituent are more effective at Methoxy substituent are more effective at parapara position than position than metameta
positionposition• Resonance effect increases electron density on the nitrogenResonance effect increases electron density on the nitrogen
N S
NH
NO CO2Me
Me
MeMeO
Me
H 159/69
• H159/69 is potent but chemically too labileH159/69 is potent but chemically too labile
N
MeMeO
Me R
N
MeMeO
Me R
N
MeMeO
Me RN
MeMeO
Me R
26. Design of omeprazole (Losec)26. Design of omeprazole (Losec)
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26.7 Substituents varied on the benzimidazole ring26.7 Substituents varied on the benzimidazole ring
• Substituents were varied to get the right balance of potency, chemical Substituents were varied to get the right balance of potency, chemical stability and synthetic accessibilitystability and synthetic accessibility
• Omeprazole was found to have the best balanceOmeprazole was found to have the best balance
• Launched in 1988 by AstraLaunched in 1988 by Astra• World’s biggest selling drugWorld’s biggest selling drug
Omeprazole
HN
N
OMe
S
O
N
MeMeO
Me
26. Design of omeprazole (Losec)26. Design of omeprazole (Losec)
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27. Esomeprazole (Nexium)27. Esomeprazole (Nexium)• Omeprazole has an asymmetric centreOmeprazole has an asymmetric centre
• The The SS-enantiomer has better potency and pharmacokinetic profile -enantiomer has better potency and pharmacokinetic profile
• Example of chiral switchingExample of chiral switching
HN
N
OMe
SN
MeMeO
Me
O
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28. Synthesis of Omeprazole28. Synthesis of Omeprazole
NCl
Pyridine portion
Me
OMe
Me
alkylchloride
+
N
NH
HS
OMe
Benzimidazole portion
thiol
NaOH
N
NH
S
OMe
N
Me
Me
MeO
N
NH
S
OMe
N
Me
Me
MeO
Omeprazole
O
O2H
OCl
meta-chloroperbenzoic acid