Omeprazole chemical structure

Eisai Co Ltd. (Japan) synthesized 4-alkoxyalkoxy-pyridine analogues of omeprazole and selected E-3810 [35], rabeprazole, as their candidate drug (Fig. 2.17). Rabeprazole, which has the 4-methoxypropoxy-3-methyl-pyridinyl moiety in its chemical structure, is largely similar to omeprazole (as are pantoprazole and lansoprazole) and has now also reached the market. 

There are currently four racemic PPIs available on the market omeprazole, lansoprazole, pantoprazole, and rabeprazole. (More recently, enantiomerically pure versions have also been studied and developed, e.g., S-omeprazole, marketed by AstraZeneca as esomeprazole see Chapter II-2.) Proton pump inhibitors share the same core structure, the substituted pyridylmethyl-sulfmyl-benzimidazole, but differ in terms of substituents on this core structure. The absolute requirements of the core structure for the activity of PPIs was not understood until it became clear that the active PPIs are derived from inactive prodrugs the prodrugs are transformed, in the acid-secreting parietal cells, by a unique cascade of chemical structural transformations leading to the active principle, a cyclic sulfenamide species. Inhibition of acid secretion in turn is then achieved by formation of covalent disulfide bonds with key cysteines of the (H+/K+)-ATPase. 

Figure 4.4a. Chemical structures of irreversible fClfC-ATPase inhibitors based on the omeprazole framework currently or previously under development.

The effect of gastric HVK -ATPase inhibitors on enzyme activity (ATP cleavage) can be studied in vitro with partly purified HVK -ATPase preparations [27]. This assay has been used more effectively to study the mechanism of action of H /K -ATPase inhibitors in detail than to study the structure-activity relationship of such inhibitors [28]. Since HVK -ATPase inhibitors of the omeprazole-type need acid activation and the enzyme assay should be performed at neutral pH values, a pre-incubation period at the lowest possible pH of about 6 was used to initiate the acidic conversion of the test compound into its active principle. This reflects more the chemical instability of the test compound at neutral pH values than its effect during conditions of much higher acidity within the secretory cannaliculus of the parietal cell during acid secretion. Many chemically labile inhibitors are therefore very active in this test system. However, they do not cause an inhibition in more complex test systems and, therefore, are without any practical usefulness [28]. 

It was soon recognized that gastric HVK -ATPase is the site of action for omeprazole [27,43] and that enzyme inhibition parallels inhibition of gastric acid secretion in laboratory animals [38]. Physico-chemically, omeprazole represents a lipid-permeable weak base with a pK of 4 [42]. At physiological pH, it is predominantly unionized and this neutral form passes freely across biological membranes. However, in an acidic environment with a pH below 4, it is predominantly protonated. This results in a limited permeability of the drug [28]. Due to the unique structure of the gastric... 

The structure-activity relationship of HVK -ATPase inhibitors of the omeprazole type is based on the balance between chemical stability at neutral pH values and acid-induced conversion into the active sulphenamide. Derivatives, which are too unstable at neutral pH, are very active in the test assay of partly purified HVK" -ATPase. This assay has been performed at pH 7.4 after preincubation at pH 6 of the enzyme protein with the derivative to be tested. The high activity was therefore the result of the conversion of the derivative in solutions of neutral pH values and this does not reflect the situation of high acidity within the secretory compartment of the parietal cell [28]. The derivatives which are very unstable at neutral pH do not inhibit gastric acid secretion in vivo because their transformation had already occurred prior to the active principle reaching the target enzyme. Chemically very stable derivatives do not show any inhibitory effect either in vitro or in vivo. 

The gastric proton-pump inhibitors currently available (Fig. 3.10) all retain the same key chemical features present in omeprazole, indicating that the structural requirements to achieve irreversible inhibition of the gastric ATPase enzyme are precisely defined. The clinical properties of this latter group of drugs is discussed more fully in section 9.6, whereas the remainder of this section focuses on other candidates currently or previously under de-... 

Banyu Pharmaceutical Co. has disclosed the properties of proton-pump inhibitors such as (4), which were obtained by chemical modification of the structure of omeprazole, but diich are reversible in their interaction with the ATPase enzyme (172). Tanabe, also, has described a proton-pump inhibitor (T-776), vdiidi contains many of the structural elements found in the irreversible inhibitors, but vdiidi has been shown to possess a reversible mechanism of action (173). 

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... 

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