Esomeprazole structure

Five proton pump inhibitors are available for clinical use omeprazole, lansoprazole, rabeprazole, pantoprazole, and esomeprazole. All are substituted benzimidazoles that resemble H 2 antagonists in structure (Figure 62-3) but have a completely different mechanism of action. Omeprazole is a racemic mixture of R- and S-isomers. Esomeprazole is the S-isomer of omeprazole. All are available in oral formulations. Esomeprazole and pantoprazole are also available in intravenous formulations (Table 62-2). 

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. 

All marketed PPIs, omeprazole, lansoprazole, pantoprazole, rabeprazole, esomeprazole, and dexlansoprazole are benzimidazole derivatives. Some new PPIs being developed have an imidazopyridine instead of the benzimidazole ring structure. 

The current proton pump inhibitors, pantoprazole, omeprazole, lansoprazole, and rabeprazole. The 2D structure of esomeprazole is the same as omeprazole, but the 3D structure differs in the orientation of the S- 0 group. 

To achieve a longer plasma half-life, an enantiomer of omeprazole has been introduced S-omeprazole, esomeprazole. These structures are shown in the figure. This has a slower metabolism than the R-enantiomer and therefore appears to have a longer dwell time in the blood. At 40-mg dosage, there appears to be improvement in pH control as compared to omeprazole as shown in the figure. 

Nexium (esomeprazole) was introduced by the pharmaceutical company AstraZenaca as a replacement for the very popular Prilosec (omeprazole) to control heartburn and acid reflux. Omeprazole is a racemic mixture and esomeprazole is the S-enantiomer (see Sidebar 5.A). The structures of the two enantiomers are shown in Figure 5.10. Note that in this molecule the chiral center is a sulfur atom, not a carbon. The structure around sulfur double bonded to oxygen (a sulfoxide) in this molecule is tetrahedral like carbon, but one of the tetrahedral coordination sites is composed of two electrons (not shown in this figure) that are not involved in bonding. 

SCHEME 48.4. Structure of esomeprazole 8 and details of the Ti(IV) mediated asymmetric sulfoxidation step. 

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