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.
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.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Proton Pump Inhibitors (ed. L. Olbe) (Birkhäuser Verlag, Basel, Switzerland, 1999).
Carlsson, E., Lindberg, P. & von Unge, S. Two of a kind. Chem. Brit. 38, 42–45 (2002).
Malen, C. E. & Danree, B. H. New thiocarboxamides derivatives with specific gastric antisecretory properties. J. Med. Chem. 14, 244–246 (1971).
Sundell, G., Sjostrand, S. E. & Olbe, L. Gastric antisecretory effects of H 83/69, a benzimidazolyl-pyridyl-methyl–sulfoxide. Acta Pharm. Tox. Suppl. 4, 77 (1977).
Lindberg, P. et al. Omeprazole, the first proton pump inhibitor. Med. Res. Rev. 10, 1–54 (1990). A comprehensive review on omeprazole.
Olbe, L. et al. Effects of a substituted benzimidazole (H 149/94) on gastric acid secretion in humans. Gastroenterology 83, 193–198 (1982).
Sjostrand, S. E., Ryberg, B. & Olbe, L. Stimulation and inhibition of acid secretion by the isolated guinea pig gastric mucosa. Acta Physiol. Scand. Spec. Suppl. 181–185 (1978).
Fellenius, E., Elander, B., Wallmark, B., Helander, H. F. & Berglindh, T. Inhibition of acid secretion in isolated gastric glands by substituted benzimidazoles. Am. J. Physiol. 243, G505–G510 (1982).
Fellenius, E. et al. A micromethod for the study of secretory function in isolated human oxyntic glands from gastroscopic biopsies. Clin. Sci. 64, 423–431 (1983).
Forte, J. G. & Lee, H. C. Gastric adenosine triphosphatases: a review of their possible role in HCl secretion. Gastroenterology 73, 921–926 (1977).
Sachs, G. et al. Metabolic and membrane aspects of gastric H+ transport. Gastroenterology 73, 931–940 (1977).
Saccomani, G., Crago, S., Mihas, A., Dailey, D. W. & Sachs, G. Tissue and cell localization of hog gastric plasma membrane by antibody techniques. Acta Physiol. Scand. (Suppl) 293–305 (1978).
Fellenius, E. et al. Substituted benzimidazoles inhibit gastric acid secretion by blocking (H+ + K+)ATPase. Nature 290, 159–161 (1981). A key paper in the elucidation of the mechanism of action of substituted benzimidazoles, such as omeprazole.
Wallmark, B., Sachs, G., Mardh, S. & Fellenius, E. Inhibition of (H+ + K+)-ATPase by the substituted benzimidazole, picoprazole. Biochim. Biophys. Acta 728, 31–38 (1983).
Larsson, H. et al. Inhibition of gastric acid secretion by omeprazole in the dog and rat. Gastroenterology 85, 900–907 (1983).
Lind, T., Cederberg, C., Ekenved, G., Haglund, U. & Olbe, L. Effect of omeprazole – a gastric proton pump inhibitor – on pentagastrin stimulated acid secretion in man. Gut 24, 270–276 (1983).
Bonnevie, O. et al. Gastric acid secretion and duodenal ulcer healing during treatment with omeprazole. Scand. J. Gastroenterol. 19, 882–884 (1984).
Lauritsen, K. et al. Effect of omeprazole and cimetidine on duodenal ulcer. A double blind comparative trial. N. Engl. J. Med. 312, 958–961 (1985).
Larsson, H. et al. Plasma gastrin and gastric enterochromaffine-like cell activation and proliferation. Studies with omeprazole and ranitidine in intact and antrectomized rats. Gastroenterology 90, 391–399 (1986).
Havu, N., Mattsson, H., Ekman, L. & Carlsson, E. Enterochromaffine-like cell carcinoids in the rat gastric mucosa following long-term administration of ranitidine. Digestion 45, 189–195 (1990).
Mattsson, H. et al. Partial gastric corporectomy results in hypergastrinemia and development of gastric ECL-cell carcinoids in the rat. Gastroenterology 100, 311–319 (1991).
Burget, D. W., Chiverton, S. G. & Hunt, R. H. Is there an optimal degree of acid suppression for healing of duodenal ulcers — a model of the relationship between ulcer healing and acid suppression. Gastroenterology 99, 345–351 (1990).
Walan, A. et al. Effect of omeprazole and ranitidine on ulcer healing and relapse rates in patients with benign gastric ulcer. N. Engl. J. Med. 320, 69–75 (1989).
Klinkenberg–Knol, E. C., Jansen, J. M., Festen, H. P., Meuwissen, S. G. & Lamers, C. B. Double-blind multicentre comparison of omeprazole and ranitidine in the treatment of reflux oesophagitis. Lancet 1, 349–351 (1987).
Havelund, T. et al. Omeprazole and ranitidine in treatment of reflux esophagitis — double-blind comparative trial. Br. Med. J. 296, 89–92 (1988).
Hetzel, D. J. et al. Healing and relapse of severe peptic esophagitis after treatment with omeprazole. Gastroenterology 95, 903–912 (1988).
Lind, T., Cederberg, C., Olausson, M. & Olbe, L. 24-hour intragastric acidity and plasma gastrin after omeprazole treatment and after proximal gastric vagotomy in duodenal ulcer patients. Gastroenterology 99, 1593–1598 (1990).
Wallmark, B., Larsson, H. & Humble, I. The relationship between gastric acid secretion and gastric H+,K+-ATPase activity. J. Biol. Chem. 260, 13681–13684 (1985).
Lindberg, P., Nordberg, P., Alminger, T., Brandstrom, A. & Wallmark, B. The mechanism of action of the gastric acid secretion inhibitor omeprazole. J. Med. Chem. 29, 1327–1329 (1986). Further elucidation of the mechnanism of action of omeprazole, revealing that a sulphenamide formed in vivo from omeprazole is the active inhibitor of the proton pump.
Besancon, M. et al. Membrane topology and omeprazole labeling of the gastric H+,K+-adenosine triphosphatase. Biochemistry 32, 2345–2355 (1993).
Lindberg, P., Brandstrom, A. & Wallmark, B. Structure–activity relationships of omeprazole analogues and their mechanism of action. Trends Pharmacol. Sci. 8, 399–402 (1987).
Im, W. B., Blakeman, D. P. & Sachs, G. Reversal of antisecretory activity of omeprazole by sulphydyryl compounds in isolated rabbit gastric glands. Biochim. Biophys. Acta. 845, 54–59 (1985).
Fujisaki, H. et al. Inhibition of acid secretion by E3810 and omeprazole, and their reversal by glutathione. Biochem. Pharmacol. 42, 321–328 (1991).
Gedda, K. et al. Turnover of the gastric H+, K+-adenosine triphosphatase α-subunit and its effect on inhibition of rat gastric acid secretion. Gastroenterology 109, 1134–1141 (1995).
Andersson, T. Pharmacokinetics, metabolism and interactions of acid pump inhibitors — focus on omeprazole, lansoprazole and pantoprazole. Clin. Pharmacokinet. 31, 9–28 (1996).
Creutzfeldt, W. Chiral switch, a successful way to drug development: example of Esomeprazole. Z. Gastroenterol. 38, 893–897 (2000). Discusses the development of single-enantiomer drugs derived from 'chiral switches' of established racemates, using esomeprazole as an example.
Katsuki, T. & Sharpless, K. B. The first practical method for asymmetric epoxidation. J. Am. Chem. Soc. 102, 5974–5976 (1980).
Kagan, H. B. & Diter, P. Asymmetric sulfoxidation — chemical and enzymatic. Organosulfur Chem. 2, 1–39 (1998).
Erlandsson, P., Isaksson, R., Lorentzon, P. & Lindberg, P. Resolution of the enantiomers of omeprazole and some of its analogues by liquid chromatography on a trisphenylcarbamoylcellulose-based stationary phase. The effect of the enantiomers of omeprazole on gastric glands. J. Chromatogr. 532, 305–319 (1990).
Lindberg, P. & von Unge, S. US Patent 5,714,504 (1988).
Cotton, H. et al. Asymmetric synthesis of esomeprazole. Tetrahedron-Asymmetry 11, 3819–3825 (2000).
Andersson, T., Rohss, K., Bredberg, E. & Hassan–Alin, M. Pharmacokinetics and pharmacodynamics of esomeprazole, the S-isomer of omeprazole. Aliment. Pharmacol. Ther. 15, 1563–1569 (2001). Describes experiments that compare S -omeprazole (esomeprazole), R -omeprazole and racemic omeprazole, which show that esomeprazole has the highest bioavailability and oral potency in inhibiting gastric acid secretion in man.
Abelo, A. et al. Stereoselective metabolism of omeprazole by human cytochrome P450 enzymes. Drug Metab. Disp. 28, 966–972 (2000).
Rohss, K., Wilder Smith, C. H., Claar Nilsson, C., Lundin, C. & Hasselgren, G. Esomeprazole 40 mg provides more effective acid control than standard doses of all other proton pump inhibitors. Gastroenterology 120, A419 (2001).
Klinkenberg-Knol, E. C. et al. Long–term omeprazole treatment in resistant gastroesophageal reflux disease: efficacy, safety, and influence on gastric mucosa. Gastroenterology 118, 661–669 (2000).
Richter, J. E. et al. Efficacy and safety of esomeprazole compared with omeprazole in GERD patients with erosive esophagitis: a randomized controlled trial. Am. J. Gastroenterol. 96, 656–665 (2001).
Lind, T. et al. Esomeprazole provides improved acid control vs. omeprazole in patients with symptoms of gastro-oesophageal reflux disease. Aliment. Pharmacol. Ther. 14, 861–867 (2000).
Castell, D. et al. Esomeprazole 40 mg compared with lansoprazole 30 mg in the treatment of erosive esophagitis. Am. J. Gastroenterol. 97, 575–583 (2002).
Kahrilas, P. J. et al. Esomeprazole improves healing and symptom resolution as compared with omeprazole in reflux oesophagitis patients: a randomized controlled trial. Aliment. Pharmacol. Ther. 14, 1249–1258 (2000).
Vakil, N. B. et al. The new proton pump inhibitor esomeprazole is effective as a maintenance therapy in GERD patients with healed erosive esophagitis. A 6-month, randomized, double blind, placebo-controlled study of efficacy and safety. Aliment. Pharmacol. Ther. 15, 926–935 (2001).
Lauritsen, K. et al. Esomeprazole 20 mg compared with lansoprazole 15 mg for maintenance therapy in patients with healed erosive esophagitis (EE). Gastroenterology 122 (Suppl 1), S 1286 (2002).
Suerbaum, S. & Michetti, P. Helicobacter pylori infection. N. Engl. J. Med. 347, 1175–1186 (2002). A review surveying scientific knowledge on Helicobacter pylori infection, focusing on the clinical aspects.
Laine, L. et al. Esomeprazole-based Helicobacter pylori eradication therapy and the effect of antibiotic resistence: results of three US multicenter, double-blind trials. Am. J. Gastroenterol. 95, 3393–3398 (2000).
Zhang, Q., Lehmann, A., Rigda, R., Dent, J. & Holloway, R. H. Control of transient lower oesophageal sphincter relaxations and reflux by the GABAB agonist baclofen in patients with gastro–oesophageal reflux disease. Gut 50, 19–24 (2002).
Skelly, M. M. & Hawkey, C. J. Potential alternatives to COX 2 inhibitors. Br. Med. J. 324, 1289–1290 (2002).
- 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.
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.
About this article
Cite this article
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
Novel magnetically retrievable In2O3/MoS2/Fe3O4 nanocomposite materials for enhanced photocatalytic performance
Scientific Reports (2021)
Clinical Drug Investigation (2021)
Nature Communications (2019)
Comparative efficacy of various anti-ulcer medications after gastric endoscopic submucosal dissection: a systematic review and network meta-analysis
Surgical Endoscopy (2019)
Frontiers of Medicine (2019)