The physiological background behind and course of development of the first proton pump inhibitor

Gastric acid secretion and its related diseases and their treatments have generated important contributions to gastroenterology and its development as an autonomous medical specialty. The discovery of histamine receptors and the subsequent H2-receptor antagonists (1972) changed the practice of gastroenterology forever. Gastric acid was effectively inhibited and ulcers could be healed to an extent which had not previously been seen. An additional milestone along the same avenue was offered by the identification of hydrogen potassium adenosine triphosphatase (H(+)K(+)-ATPase) as the proton pump of the parietal cell. Nowadays, proton pump inhibitors (PPIs) are widely used. However, we need to reconsider the physiology and pathophysiology of acid secretion and its long-term inhibition to avoid potential negative effects on general health. PPIs are generally considered among the safest class of drugs. In the late 1960s, a research project was initiated to develop an antisecretory drug which could be used in acid hypersecretory disease states such as peptic ulcer disease based on the option to synthesize a local anesthetic drug that could be orally administered and therefore have its main action on the gastrin cells. This concept was soon found to be a blind track and further development of the basic compounds CMN131 by the synthesis of H77/67 were found to be active in the gastric acid secretion, and the benzimidazol analog of H77/67 was then synthesized a year later and was tested and found to exert powerful acid inhibitory effects. Binding studies with the substituted benzimidazoles clarified specific binding to H+/K+/ATPase in the secretory vesicles of the parietal cells. Since weak bases like aminopyrine accumulate in the acid compartment of the parietal cells, the chemists changed the substituents of the heterocyclic ring and obtained a compound with a weak base property with an optimal PkA value, thereby maximizing the accumulation of the compound at the site of action. This compound H168/68 was synthesized in 1979 and was given the generic name omeprazole. Omeprazole was soon shown to be a very potent inhibitor of the proton pump in vitro as well as in preparation from the human stomach tissue. Pharmacological studies showed long-lasting effect on acid secretion and a specific binding to the target site and soon found the compound to exert unique therapeutic effects.

The development of the first PPI omeprazole represents an exceptional example of a unique and fruitful collaboration between people with in-depth knowledge of gastric physiology and pharmacology. Frontline expertise in biochemistry and applied clinical science were added to these components, resulting in one of the greatest therapeutic advances during the last decades of the former century.