Proton Pump Inhibitors

PPIs were introduced in 1989, the culmination of serendipity and drug design. It is probably correct to state that without the serendipity, the PPIs would never have been designed. Hassle AB in Sweden had for some years a program for the discovery of anti-ulcer drugs using the classic rat ulcer model and measurement of acid secretion. Pyridinyl-2-ethylamide was found to inhibit acid secretion. Modification to pyridinyl-2-ethylthioamide maintained inhibition of acid secretion, but the mechanism was unknown, and remains so. With the discovery of cimetidine, there was speculation that pyridinyl-2-ethylamide might be an H2 receptor antagonist. 2-(Pyridinylmethylthio)benzimidazole was made, and then modified to generate 2-(pyridinylmethylsulfinyl) benzimidazole (timoprazole; Figure 2) to development.

Figure 1 The structure of histamine, cimetidine, ranitidine, and famotidine, showing the retention of the imidazole structure in cimetidine, replaced by a furan ring in ranitidine and a thiazole ring in famotidine.

NCN Cimetidine

Histamine

Ranitidine

Famotidine

Figure 1 The structure of histamine, cimetidine, ranitidine, and famotidine, showing the retention of the imidazole structure in cimetidine, replaced by a furan ring in ranitidine and a thiazole ring in famotidine.

Figure 2 Compounds leading to the synthesis of omeprazole, the first PPI.

Pyridinyl-2-ethylamide

Pyridinyl-2-ethylthioamide

2-Pyridylmethythio-benzimidazole

Timoprazole (1975)

Figure 2 Compounds leading to the synthesis of omeprazole, the first PPI.

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