Proton-pump inhibitors are a group of medications whose main action is a pronounced and long-lasting reduction of stomach acid production. Within the class of medications, there is no clear evidence that one agent works better than another. They are the most potent inhibitors of acid secretion available.

1. PROTON PUMP INHIBITORS
Md. Saiful Islam
B.Pharm, M.Pharm (PCP)
North South University
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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