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Patrick
An Introduction to Medicinal Chemistry 3/e
Chapter 22
ANTIULCER AGENTS
Part 3: Proton pump inhibitors
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Contents
Part 3: Proton pump inhibitors
23.
24.
25.
26.
Parietal Cells and the Proton Pump
Proton Pump Inhibitors
Mechanism of inhibition
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]
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23. Parietal Cells and the Proton Pump
M3
H2
Cck2
ATP
ADP + Pi
Receptors
Proton pump
H+ K+
Cl
Canaliculus
The proton pump
•
•
•
•
•
•
•
HCl
Ion channels
-
Lumen of the stomach
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
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24. Proton Pump Inhibitors
methylsulfinyl
benzamidazole
'linker'
H
OCHF2
N
pyridine O
N
S
N
MeO
H
N
O
N
S
N
Me
OMe
OMe
MeO
Omeprazole
Me
Pantoprazole
H
N
O
N
S
N
S
N
O
F3C
N
Me
O
Lansoprazole
MeO
•
•
Na
N
O
Me
Rabeprazole
Act as prodrugs
Activated by strongly acidic conditions found in the canaliculae
of parietal cells
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25. Mechanism of inhibition
Me
O
Me
Me
N
O
N
S
N
Me
-H+
N
H
NH
S
H
N
OMe
Me
Me
H+
N
H
N
S
OMe
OMe
OMe
O
OMe
H
N
H
OMe
Spiro intermediate
H
OMe
OMe
OMe
H
N
-H2O
N
N
HS
N
N
N
H
S
Me
Me
S
MeO
OH
Me
Sulfenic acid intermediate
Proton
pump
MeO
Me
Pyridinium sulfenamide structure
N
NH
N
S
Me
MeO
Me
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S
Proton
pump
26. Design of omeprazole (Losec)
26.1. The lead compound
N
S
NH2
CMN 131
•
•
•
Originally an antiviral drug
Inhibits gastric acid secretion
Liver toxicity due to the thioamide group
26.2. Modification of the thiourea group
N
N
S
N
H
H 77/67
•
•
Inhibits gastric acid secretion
The pyridine ring and bridging CH2S moiety are important to activity
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26. Design of omeprazole (Losec)
26.3 Modify the imidazole ring
benzimidazole
pyridine
N
N
S
N
H
H 124/26
•
Increase in activity due to the benzimidazole ring
26.4 Drug metabolism studies
O
N
N
S
N
H
Timoprazole
•
•
•
•
Timoprazole formed by metabolism of H124/26
Timoprazole is the active drug
Pyridinylmethylsulfinyl benzimidazole structure
Side effect - inhibits iodine uptake by the thyroid gland
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26. Design of omeprazole (Losec)
26.5 Add substituents to the heterocyclic rings
O
N
CO2Me
N
H
Me
S
Me
•
•
•
N
Picoprazole
Potent antisecretory properties over long periods of time
No toxic side effects on the thyroid
No other serous side effects
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26. Design of omeprazole (Losec)
26.6 Substituents varied on the pyridine ring
O
N
•
N
H
Me
Me
H 159/69
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
•
•
•
•
N
N
Me
R
MeO
•
CO2Me
S
Me
MeO
N
Me
Me
MeO
N
N
R
Me
Me
MeO
H159/69 is potent but chemically too labile
R
Me
Me
R
MeO
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Me
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
H
N
O
N
S
N
Me
MeO
•
•
OMe
Me
Omeprazole
Launched in 1988 by Astra
World’s biggest selling drug
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27. Esomeprazole (Nexium)
•
Omeprazole has an asymmetric centre
•
The S-enantiomer has better potency and pharmacokinetic profile
•
Example of chiral switching
N
O
OMe
S
N
Me
MeO
H
N
Me
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28. Synthesis of Omeprazole
OMe
Me
Pyridine portion
N
H
Me
Benzimidazole portion
N
Cl
S
Me
MeO
O
N
OMe
S
N
H
Me
O
N
NaOH
N
H
Cl
alkyl
chloride
N
OMe
N
thiol
+
HS
Me
N
O2H
meta-chloroperbenzoic acid
MeO
Me
Omeprazole
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OMe