Omeprazole design

AD-9161 represents the most potent of a novel but mechanistically similar class of irreversible H /K -ATPase inhibitors (134). Compounds of this type were designed based on the finding that the oxoisothiazolo[5,4-6]pyridine (3) displayed potent inhibition of ATPase in vitro but failed to achieve inhibition of gastricacid secretion in vivo (135). This disparity was ascribed to the rapid and preferential attachment to and inactivation of (3), by thiol groups located outside the region of the ATPase enzyme in the parietal cells. AD-9161 is considerably more stable than (3)and displays potency comparable to that of omeprazole both in vitro and in vivo. 

The core structure of all the clinically approved PPIs is timoprazole. Although effective as an acid-suppressive agent, this molecule was unstable at neutral pH, as well as exhibited thyrotoxic and thymotoxic effects. This led to the development of similar chemical moieties that were not only stable at neutral pH, but also exhibited no organ toxicity. The arrows show the position of substitution of different groups to produce the different PPIs now on the market. The initial substitutions designed for omeprazole resulted in the... 

Although the principles above appear to be logical design features for novel H, K -ATPase inhibitors and the patent literature describing compounds of this class is extensive, only four such compounds have found clinical utility today (Fig. 1). This implies that even though many compounds meet the basic design features of omeprazole, their intrinsic toxicity or pharmacokinetic properties are not satisfactory. The long period of research and development needed for omeprazole described elsewhere is indicative of the hurdles in this respect. 

Rabeprazole is a new PPI that has been approved for clinical use in Japan and is undergoing late-phase clinical trials in Europe and North America. Although rabeprazole was designed to be more potent than omeprazole for suppressing gastric acid secretion, it appears to dissociate more quickly and completely from H, K -ATPase than omeprazole or lansoprazole, suggesting a partially reversible inhibition of the proton pump [83]. Currently, published information on rabeprazole is scarce and mainly comes from animal studies and a limited number of studies performed in humans which have been published in abstract form only [83]. 

Omeprazole is clearly the most thoroughly investigated PPI in H. pylori eradication therapy. Its effectiveness in combination with antimicrobials has been proven in a series of well-designed studies. The use of pantopra-zole and lansoprazole in H. pylori eradication therapy have subsequently also been well documented (Tab. 3). 

This study was conducted according to the same design as the OMNIUM study. Five hundred and forty-one patients on continuous NSAID therapy who presented with ulceration and/or more than 10 erosions (in either stomach or duodenum) were randomised to receive omeprazole 20 or 40 mg mane or ranitidine 150 mg bd as healing therapy over 4 or 8 weeks. The 432 patients achieving treatment success (as defined above) were rerandomised to receive omeprazole 20 mg or ranitidine 150 mg bd or 6 months. 

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