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.

Review article: the continuing development of proton pump inhibitors with particular reference to pantoprazole.

Compounds represented by formula (Ia) are disclosed by the invention, along with compositions and complexes thereof, optionally in combination with compounds of formula (Ib). Pharmaceutical formulations and methods of making and using such compounds are also disclosed.

Alkoxy substituted benzimidazole compounds, pharmaceutical preparations containing the same, and methods of using the same

The invention concerns configurationally homogeneous, enantiomerically pure pyridylmethylsulphinyl-1H-benzimidazoles, a method of preparing them, and new intermediates necessary for the preparation.

Separation of enantiomers

Proton pump inhibitors of the benzimidazole type exert a specific antibacterial activity against Helicobacter pylori in vitro. In the present study, the basis for this selectivity was investigated, and in particular, various factors affecting the in vitro antibacterial activity of sulfide analogs of benzimidazoles were studied. Upon preincubation of omeprazole for a period of up to 72 h in a buffer at pH 7, a product was formed that was bactericidal for H. pylori but had no effect on urease activity. Sulfide constitutes the main end product of degradation. The sulfide analog of omeprazole (H 168/22) exerted a bactericidal activity specifically against both resting (in buffer) and growing (in broth) Helicobacter spp., and time-kill in buffer at pH 5 was enhanced compared to that at pH 7. There was no or very low covalent binding of 3H-labeled H 168/22 to Helicobacter spp. or to other gram-negative and gram-positive bacteria. In the presence of fetal calf serum (FCS) under the same conditions, binding was only slightly lowered while the killing activity was markedly reduced, indicating a probably nonspecific interaction with proteins and/or protection of bacterial target(s) by FCS. Addition of H 168/22 (four times the minimum bactericidal concentration [MBC]) to exponentially growing H. pylori immediately stopped growth, and after an incubation period of 20 h viable counts were reduced by >7 log10. One-hour exposure of H. pylori to the drug followed by repeated washing retarded growth by about 2 h, indicating that the effect is reversible after short-term exposure. MICs and MBCs of various sulfide structures were lower than those obtained in broth after the addition of the corresponding sulfoxide. Thus, the MBC of the sulfide structure of omeprazole against 140 clinical isolates of H. pylori ranged from 8 to 32 microg/ml, compared to an MBC of omeprazole of 32 to 128 microg/ml. A similar potency was also recorded against other helicobacters. In conclusion, formation of sulfides of benzimidazoles in culture media is the reason for the selective antibacterial effect against H. pylori. The sulfides rapidly exerted a reversible antibacterial activity, which was specific against both resting and growing Helicobacter spp. without any covalent protein binding.

Basis for the selective antibacterial activity in vitro of proton pump inhibitors against Helicobacter spp.

Dry-blend pharmaceutical formulations

Chemical Reactions of Omeprazole and Omeprazole Analogues. Part 5. The Reaction of N-Alkylated Derivatives of Omeprazole Analogues with 2-Mercaptoethanol.

Chemical Reactions of Omeprazole and Omeprazole Analogues. Part 2. Kinetics of the Reaction of Omeprazole in the Presence of 2-Mercaptoethanol.

Chemical Reactions of Omeprazole and Omeprazole Analogues. Part 1. A Survey of the Chemical Transformations of Omeprazole and Its Analogues

Chemical Reactions of Omeprazole and Omeprazole Analogues. Part 4. Reactions of Compounds of the Omeprazole System with 2-Mercaptoethanol.

Chemical Reactions of Omeprazole and Omeprazole Analogues. Part 3. Protolytic Behavior of Compounds in the Omeprazole System

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