After treatment of millions of patients suffering from gastroesophageal reflux disease (GERD) and other acid-related ailments with proton pump inhibitors, there are still unmet medical needs such as rapid and reliable pain relief, especially for nocturnal acid breakthrough. In this work, we introduce and characterize the biochemistry and pharmacology of the potassium-competitive acid blocker (P-CAB) soraprazan, a novel, reversible, and fast-acting inhibitor of gastric H,K-ATPase. Inhibitory and binding properties of soraprazan were analyzed together with its mode of action, its selectivity, and its in vivo potency. This P-CAB has an IC 50 of 0

[(Pyridylmethyl)sulfinyl]benzimidazoles 1 (PSBs) are a class of highly potent antisecretory (H+,K+)-ATPase inhibitors which need to be activated by acid to form their active principle, the cyclic sulfenamide 4. Selective inhibitors of the (H+,K+)-ATPase in vivo give rise to the nonselective thiophile 4 solely at low pH, thus avoiding interaction with other thiol groups in the body. The propensity to undergo the acid-catalyzed transformation is dependent on the nucleophilic/electrophilic properties of the functional groups involved in the formation of 2 since this step is both rate-determining and pH-dependent. The aim of this study was to identify compounds with high (H+,K+)-ATPase inhibitory activity in stimulated gastric glands possessing acidic pH, but low reactivity (high chemical stability) at neutral pH as reflected by in vitro (Na+,K+)-ATPase inhibitory activity. The critical influence of substituents flanking the pyridine 4-methoxy substituent present in all derivatives was carefully studied. The introduction of a 3-methoxy group gave inhibitors possessing a combination of high potency, similar to omeprazole and lansoprazole, but increased stability. As a result of these studies, compound 1a (INN pantoprazole) was selected as a candidate drug and is currently undergoing phase III clinical studies.

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Cross-linking and two-dimensional crystallization studies have suggested that the membrane-bound gastric H,K-ATPase might be a dimeric alpha,beta-heterodimer. Effects of an oligomeric structure on the characteristics of E(1), E(2), and phosphoenzyme conformations were examined by measuring binding stoichiometries of acid-stable phosphorylation (EP) from [gamma-(32)P]ATP or (32)P(i) or of binding of [gamma-(32)P]ATP and of a K(+)-competitive imidazonaphthyridine (INT) inhibitor to an enzyme preparation containing approximately 5 nmol of ATPase/mg of protein. At <10 microM MgATP, E(1)[ATP].Mg.(H(+)):E(2) is formed at a high-affinity site, and is then converted to E(1)P.Mg.(H(+)):E(2) and then to E(2)P.Mg:E(1) with luminal proton extrusion. Maximal acid-stable phosphorylation yielded 2.65 nmol/mg of protein. Luminal K(+)-dependent dephosphorylation returns this conformation to the E(1) form. At high MgATP concentrations (>0.1 mM), the oligomer forms E(2)P.Mg:E(1)[ATP].Mg.(H(+)). The sum of the levels of maximal EP formation and ATP binding was 5.3 nmol/mg. The maximal amount of [(3)H]INT bound was 2.6 nmol/mg in the presence of MgATP, Mg(2+), Mg-P(i), or Mg-vanadate with complete inhibition of activity. K(+) displaced INT only in nigericin-treated vesicles, and thus, INT binds to the luminal surface of the E(2) form. INT-bound enzyme also formed 2.6 nmol of EP/mg at high ATP concentrations by formation of E(2).Mg.(INT)(exo):E(1)[ATP].Mg.(H(+)) which is converted to E(2).Mg.(INT)(exo):E(1)P.Mg.(H(+))(cyto), but this E(1)P form was K(+)-insensitive. Binding of the inhibitor fixes half the oligomer in the E(2) form with full inhibition of activity, while the other half of the oligomer is able to form E(1)P only when the inhibitor is bound. It appears that the catalytic subunits of the oligomer during turnover in intact gastric vesicles are restricted to a reciprocal E(1):E(2) configuration.

SUMMARY Inhibition of the gastric proton pump is gaining acceptance as the treatment of choice for severe gastrooesophageal reflux disease, and for treatment of duodenal and gastric ulceration. Three of these drugs are now available (omeprazole, lansoprazole and pantoprazole) and more are being developed. Proton pump inhibitors share the same core structure, but differ in terms of substituents on this core. The substitutions are able to modify some important chemical properties of the compounds. For example, pantoprazole is significantly more acid‐stable than omeprazole or lansoprazole. E3810 is significantly less stable than the other compounds. We present an explanation for this finding that depends on the relative pK values for the pyridine and benzimidazole nitrogens, especially the former. Pantoprazole formulated in an enteric‐coated tablet displays high bioavailability and linear pharmacokinetics whether on single or multiple dose regimens. Although all three proton pump inhibitors provide a similar chemical conversion to sulphenamides, which are highly reactive cysteine reagents, these reagents derivatize different cysteines in the extracytoplasmic or membrane domain of the pump and inhibit the pump at different rates. Whereas the differences in chemical reactivity can be explained by the solution chemistry of the compounds, selective derivatization of different cysteines on the protein argues for an involvement of pump structure in response to the presence of the proton pump inhibitor on its luminal surface. This suggests that the proton pump inhibitors, which were originally designed to take advantage of only the highly acidic space generated in the parietal cell by the production of the sulphenamide, are made even more selective by the protein they target. Pantoprazole is metabolized by a combination of phase I and phase II metabolism, and has also been shown to have a very low potential for drug interaction. Studies of acid secretion in man have shown this compound to be an effective and long lasting inhibitor of acid secretion. The pharmacodynamics explain the cumulative effect of repeated doses and maximal acid secretory capacity with a once daily dosage.