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Concept
Discovery and development of proton pump inhibitors
Summary
Proton pump inhibitors (PPIs) block the gastric hydrogen potassium ATPase (H+/K+ ATPase) and inhibit gastric acid secretion. These drugs have emerged as the treatment of choice for acid-related diseases, including gastroesophageal reflux disease (GERD) and peptic ulcer disease.
PPIs also can bind to other types of proton pumps such as those that occur in cancer cells and are finding applications in the reduction of cancer cell acid efflux and reduction of chemotherapy drug resistance.
Evidence emerged by the end of the 1970s that the newly discovered proton pump (H+/K+ ATPase) in the secretory membrane of the parietal cell was the final step in acid secretion. Literature from anaesthetic screenings led attention to the potential antiviral compound pyridylthioacetamide which after further examination pointed the focus on an anti-secretory compound with unknown mechanisms of action called timoprazole. Timoprazole is a pyridylmethylsulfinyl benzimidazole and appealed due to its simple chemical structure and its surprisingly high level of anti-secretory activity.
Optimization of substituted benzimidazoles and their antisecretory effects were studied on the newly discovered proton pump to obtain higher pKa values of the pyridine, thereby facilitating accumulation within the parietal cell and increasing the rate of acid-mediated conversion to the active mediate. As a result of such optimization the first proton pump inhibiting drug, omeprazole, was released on the market.
Other PPIs like lansoprazole and pantoprazole would follow in its footsteps, claiming their share of a flourishing market, after their own course of development.
PPIs can be divided into two groups based on their basic structure. Although all members have a substituted pyridine part, one group has linked to various benzimidazoles, whereas the other has linked to a substituted imidazopyridine. All marketed PPIs (omeprazole, lansoprazole, pantoprazole) are in the benzimidazole group.
Proton pump inhibitors are prodrugs and their actual inhibitory form is somewhat controversial.
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