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A proton-pump inhibitor expedition: the case histories of omeprazole and esomeprazole

Key Points

  • Inappropriate levels of gastric acid underlie several widespread pathological conditions, including gastroesophageal reflux disease (GERD) and peptic ulcers.

  • Control of the complex mechanism of gastric acid secretion has thus long been a goal for the management of such diseases.

  • This article describes the key discoveries and challenges in the discovery and development of omeprazole, the first in a class of antisecretory drugs that act by inhibiting the proton pump in the acid-secreting parietal cells of the stomach, activation of which is the final step in acid secretion.

  • Omeprazole concentrates specifically in the acidic canalicular space of the parietal cells of the stomach, where it is converted to the active inhibitor of the proton pump — a sulphenamide that forms a covalent complex with the pump.

  • Omeprazole is a very potent inhibitor of gastric acid secretion, with a long-lasting duration of action. In clinical studies, it proved superior to previous treatments for GERD and peptic ulcers.

  • However, omeprazole shows significant inter-individual variability in pharmacokinetics and effect on acid secretion, which lead to the initiation of a new discovery programme to find a drug with improved biovailability compared with omeprazole.

  • This resulted in the discovery that the S-isomer of omeprazole — esomeprazole — had higher bioavailability and oral potency in inhibiting gastric acid secretion owing to stereoselective metabolism.

  • Esomeprazole has been shown to be clinically superior to other proton-pump inhibitors in GERD, the most common acid-related disease. Esomeprazole in combination with antibiotics to eliminate Helicobacter pylori infection — now known to be the cause of most peptic ulcers — yields high healing rates.

Abstract

Thirty years ago, disorders associated with inappropriate levels of gastric acid were a major problem for which treatment options were limited, and approaches to the control of gastric acid secretion were thus the focus of considerable drug discovery efforts. Here, we summarize how one such programme led to the development of the proton-pump inhibitor omeprazole (Losec, Prilosec), a conceptually new drug that proved clinically superior to previous antisecretory drugs in the treatment of acid-related disorders, and which became the world's best-selling drug in the late 1990s. We then describe how the antisecretory and clinical effects were further improved by the development of esomeprazole (Nexium), a single enantiomer of omeprazole, which was launched in 2000.

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Figure 1
Figure 2: Proton-pump inhibition.
Figure 3: Synthesis of omeprazole and esomeprazole.
Figure 4: Effects of racemic omeprazole and its enantiomers.
Figure 5: Optimal dosing of esomeprazole.

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Correspondence to Lars Olbe.

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FURTHER INFORMATION

Encyclopedia of Life Sciences

Ion motive ATPases: V- and P-types ATPases

ATPases: Ion motive

Glossary

GASTROESOPHAGEAL REFLUX DISEASE

Any symptomatic clinical condition with or without change in tissue structure that results from the reflux of gastric acid into the esophagus.

HEARTBURN

A burning sensation starting in the upper part of the abdomen and moving through the chest towards the throat.

PEPTIC ULCERS

Ulcers in the upper gastrointestinal tract, in which gastric acid is a key promoter.

GASTRIC FISTULA DOGS

Dogs provided with a cannula into the stomach or into separated pouches of the stomach.

NECROTIZING VASCULITIS

An immunologically induced process causing an inflammatory reaction and necrosis in blood vessels.

ENANTIOMERIC EXCESS

If one enantiomer is present to a greater extent, an enantiomeric excess exists where: enantiomeric excess = (measured specific rotation of mixture/specific rotation for the pure enantiomer) × 100.

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Olbe, L., Carlsson, E. & Lindberg, P. A proton-pump inhibitor expedition: the case histories of omeprazole and esomeprazole. Nat Rev Drug Discov 2, 132–139 (2003). https://doi.org/10.1038/nrd1010

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