Proton pump inhibitors structure

Omeprazole is an antiulcer drug. It is a proton pump inhibitor. This substituted benzimidazole inhibits gastric acid secretion to help acid/peptic disorders and duodenal ulcers. It interferes with the proton pump in the mucous lining of the stomach, the last stage of acid production. It can turn off stomach acid in as little as one hour. Lansoprazole (no. 12) has a similar structure. 

These agents are second generation proton pump inhibitors. Their mode of action is similar to omeprazole. Structural differences give more rapid absorption and greater bioavailability of lansoprazole. Lansoprazole has less effect on P-450 enzymes, while interaction with pantoprazole is insignificant. Lansoprazole has a significant antibacterial effect on Helicobacter pylori. 

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). 

Proton pump inhibitors undergo rapid first-pass and systemic hepatic metabolism and have negligible renal clearance. Dose reduction is not needed for patients with renal insufficiency or mild to moderate liver disease but should be considered in patients with severe liver impairment. Although other proton pumps exist in the body, the H+,K+ ATPase appears to exist only in the parietal cell and is distinct structurally and functionally from other H+ -transporting enzymes. 

Roche [168] pointed out that omeprazole and other proton pump inhibitors bind strongly to serum proteins and are extensively metabolized by the CYP450 family of enzymes. The CYP2C19 isoform is important in converting parent structures to inactive metabolites, although CYP3A4 also plays a role in the proton pump inhibitors biotransformation. The metabolic degradation pathways for omeprazole are shown in Scheme 4.2. 

The proton pump inhibitor nepaprazole is a racemate. Draw the structural formulae of both -configured isomers. 

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. 

Choudhry U, Boyce HW Jr, Coppola D. Proton pump inhibitor-associated gastric polyps a retrospective analysis of their frequency, and endoscopic, histologic, and ultra-structural characteristics. Am J Clin Pathol 1998 110(5) 615-21. 

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 benzimidazole scaffold is a useful structural motif for the development of molecules of pharmaceutical or biological interest. Appropriately substituted benzimidazole derivatives have foimd diverse therapeutic apphcations such as in antiulcers, antihypertensives, antivirals, antifungals, anticancers, and antihistaminics [3]. The optimization of benzimidazole-based structures has resulted in various drugs that are currently on the market, such as omeprazole 1 (proton pump inhibitor), pimobendan 2 (ionodilator), and mebendazole 3 (anthelmintic) (Fig. 1). The spectrum of pharmacological activity exhibited by benzimidazoles has been reviewed by several authors [3-6]. 

Figure 18.1 Structures of the proton pump inhibitors omeprazole (racemate) and esomepra-zole (S-enantiomer).

Interestingly, some histamine Hj-receptorantagonists, like ranitidine or nizatidine, in spite of their different pharmacological profile, showa certain structural relationship to nitenpyram (Fig. 8.48). Prior to the discovery of proton-pump inhibitors, these were the most important drugs for the treatment of stomach ulcers. 

Table 14.1 Chemical structures of benzimidazole proton pump inhibitors (PPIs) showing the timoprazole backbone stmcture and structure of tenatoprazole, a new generation imidazopyridine PPI...

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. 

Shamburek RD, Schubert ML (1994) Structure and function of the stomach. Role of the proton pump. In RH Hunt (ed) Proton pump inhibitors and acid-related diseases. Adis International, Osaka... 

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