1. PROTON PUMP INHIBITORS
Medicinal Chemistry - III
B. Pharm.
Dr Pran Kishore Deb and Dr. Bilal Al-Jaidi

2. Learning Outcomes At the end of the lecture students will be able to
Understand where and how drugs work
Understand principles of how drugs are designed
Understand process of how drugs are designed
Illustrate drug design and development of proton pump inhibitors using examples
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3. Parietal Cells and the Proton Pump
Gastric juices consists of digestive enzymes and hydrochloric acid designed to break down food
Hydrochloric acid is secreted from parietal cells and the stomach secrets a layer of mucus to protect itself from its own gastric juices
The protons required for HCl are generated from water and carbon dioxide catalysed by an enzyme called carbonic anhydrase
Once proton have been generated, they have to be exported out of the cells rather than stored because of two reasons:
build up of acids within cells would be harmful to the cell
Enzyme catalysed reaction which generates protons is reversible
The export of protons from the parietal cells is achieved by an enzyme complex called the proton pump or H+/ K+-ATPase
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4. Parietal Cells and the Proton Pump
Histamine
Acetylcholine
Gastrin
Lumen of the stomach
Proton pump
Receptors
Ion channels
Cck2 H2 M3
ATP
ADP + Pi H +
Parietal cell + K
HCl Cl -
Canaliculus
When the parietal cells are actively secreting HCl into the stomach, they form invaginations called canaliculus.
Proton pump is present in the canalicular membrane of parietal cells
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
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5. Parietal Cells and the Proton Pump
Proton pump is not responsible for the efflux of chloride ion
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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6. Parietal Cells and the Proton Pump
The acetylcholine (neurotransmitter), histamine (hormone) and the gastrin (hormone) activate the cholinergic receptor, Gastrin-receptor and H2-receptor of the parietal cells which in turn activates proton pump leading to the release of gastric acid into stomach
The trigger for this process is provided by the sight, smell, or even thought of food
Thus gastric acid is released before food has even entered the stomach
Release of gastric acid can be inhibited by antagonists blocking either the cholinergic receptor or the receptor for Gastrin
Unfortunately these antagonists also block the acetylcholine receptors at other part of the body and cause unwanted side effects
Similarly the histamine antagonists have proved to be important antiulcer drug but they have now largely been suppressed by PPIs which blocks the mechanism by which HCl is released from parietal cells
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7. Design and Development of Proton Pump Inhibitors
It was seen by Swedish scientists that local anaestetics related to lignocaine reduce gastric acid secretion in man when taken orally
Then the Swedish scientists attended a conference where they discovered that a potential antiviral drug called pyridylthioacetamide slowed down gastric secretion as a side effect
This drug was toxic due to thioacetate group
To overcome this other S-C-N groups were investigated and H 77/67 was discovered which had antisecretory activity
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8. Structural variants of H77/67 were prepared in the quest for a better compound
This work culminated in the discovery of the benzimidazole compound H 124/26
Metaboilsm studies showed that H 124/26 formed a more potent sulphoxide called timoprazole
It turned out that timoprazole prevented uptake of iodine by the thiroid
More analogues were prepared and picoprazole was found to be free from side effects
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9. More potent analogues were sought
This was achieved by increasing the pKa of the pyridine ring by placing electron donating groups on it
A promising, but unstable, analogue H 159/69 was formed
This led to the discovery of its analogue omeprazole
OM Launched in 1988 by Astra - World’s biggest selling drug
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10. Effect of Substituents 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

11. OM is absorbed from the duodenum into the circulation
OM has a pKa of 4.0 (benzimidazole) and 8.7 (pyridine)
So in blood stream (pH 7.6) benzimidazole is unionised
In neutral form OM has log P of 2.23
This allows it to diffuse through the fatty secretary canals of the parietal cells (as in equilibrium)
The pH of the parietal cells is very low (~1.0)
This causes OM to be completely ionized
In this ionised form OM cannot diffuse back out of the cell
This is known as “Ion Trapping”
The result is a build up in concentration of OM
Chemical conversion of OM then occurs !!
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12. Mechanism of Proton Pump Inhibition by Omeprazole

13. Mechanism of Proton Pump Inhibition by Omeprazole
Pyridine first ionised (pKa = 8.7) by acid environment
Then in equilibrium the imidazole is protonated
Very rapidly the lone pair on pyridine N attacks edeficient 2-carbon atom of the benzimidazole ring
This C sits between 2 N atoms one of which has a + charge which want to loose
Ring system wants to regain aromaticity because it is energetically favourable
It does this by forming the sulphenic acid
Lone pair on N attackes the neighbouring S atom
This causes the loss of water which gives the sulphenamide
There is maximal conversion to the sulphenamide due to the steep proton gradient caused by the H+/K+- ATPase enzyme
There is ion trapping of both OM and the sulphenamide
This is why the drug acts specifically in the parietal cells
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14. Mechanism of Proton Pump Inhibition by Omeprazole
Sulphenamide reacts with thiol groups in H+/K+- ATPase enzyme which forms a stable disulphide complex
No more acid is produced until new enzyme is made which results in long duration of inhibition of gastric acid production
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OM used to treat duodenal ulcers and erosive oesophagitis

15. Mechanism of Proton Pump Inhibition by Omeprazole
OM used to treat duodenal ulcers and erosive oesophagitis
OM is formulated in hard gelatin capsules (enteric coated) to prevent conversion to the sulphenamide whilst in the stomach.
Any sulphenamide formed would react with thiols in food and gastric mucus and be charged rendering it unavailable
Uncharged OM is absorbed from the small intestine into the circulation and then diffuses into the parietal cells
High does ( 80mg) of OM can almost completely abolish gastric acid production for at least 4 hours
Patients are given 20mg doses daily for 2-4 weeks (duodenal ulcer) or up to 8 weeks (gastric ulcer)
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Omeprazole is a chiral compound and has an asymmetric centre
The S-enantiomer has better potency and pharmacokinetic profile

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

17. Summary OM localises in parietal cells where stomach acid is produced
It inhibits H+ /K+- ATPase enzyme which catalyses the final step of stomach acid production
In its unionised form it is absorbed into the blood from the duodenum
As it’s benzimidazole has a pKa = 4.0 it remains in equilibrium in the blood (pH = 7.6) with a logP = 2.23
Having a logP = 2.23 allows OM to diffuse though the fatty parietal cell where there is a pH = 1.0
OM then ionises and becomes “trapped” and a build up in concentration of the drug occurs
Once in the ionised form a chemical conversion occurs which turns OM into the suphenamide (active form)
Sulphenamide reacts with H+/K+-ATPase enzyme and stops acid production
As no more acid can be produced until more enzyme is made OM has a long lasting action
OM is a chiral molecule with the S-enantiomer being the active stereoisomer which was introduced to the clinic
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18. Thank you…….. 
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