[(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.

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.

The solution structure of a recombinant mutant [rSP‐C (FFI)] of the human surfactant‐associated protein C (hSP‐C) in a mixture of chloroform and methanol was determined by high‐resolution NMR spectroscopy. rSP‐C (FFI) contains a helix from Phe5 to the C‐terminal Leu34 and is thus longer by two residues than the helix of porcine SP‐C (pSP‐C), which is reported to start at Val7 in the same solvent. Two sets of resonances at the C‐terminus of the peptide were observed, which are explained by low‐order oligomerization, probably dimerization of rSP‐C (FFI) in its α‐helical form. The dimerization may be induced by hydrogen bonding of the C‐terminal carboxylic groups or by the strictly conserved C‐terminal heptapeptide segment with a motif similar to the GxxxG dimerization motif of glycophorin A. Dimerization at the heptapeptide segment would be consistent with findings based on electrospray ionization MS data, chemical cross‐linking studies, and CNBr cleavage data.

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