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

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 8/1/2019

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 8/1/2019

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 8/1/2019

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 8/1/2019

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 8/1/2019

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 8/1/2019

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 8/1/2019

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 8/1/2019

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

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 !! 8/1/2019

Mechanism of Proton Pump Inhibition by Omeprazole

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 8/1/2019

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 8/1/2019 OM used to treat duodenal ulcers and erosive oesophagitis

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) 8/1/2019 Omeprazole is a chiral compound and has an asymmetric centre The S-enantiomer has better potency and pharmacokinetic profile

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

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 8/1/2019

Thank you……..  8/1/2019