Proton-pump inhibitors benzimidazole

Benzimidazole is an important heterocyclic nucleus in the field of medicinal chemistry. The most prominent benzimidazole compound in nature is N-ribosyldimethylbenzimidazole, which serves as an axial ligand for cobalt in vitamin B12. The versatile nature of benzimidazole makes it a highly explored molecule in medicinal chemistry. A number of pharmacological activities are associated with benzimidazole derivatives such as anthelmintic, antiulcer, antipsychotic, proton pump inhibitor, antianxiety, anti-emetic and sedative, vasodilator, anticancer, analgesic, antihistaminic, antifungal, antiviral and antimicrobial. 

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. 

Rabeprazole belongs to substituted benzimidazole proton-pump inhibitors. In gastric parietal cells, rabeprazole is proto-nated, accumulates and is transformed to an active sulfenamide. 

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). 

Pantoprazole sodium, a substituted benzimidazole derivative, is an irreversible proton pump inhibitor, and was developed for the treatment of acid-related gastrointestinal disorders. As with other drugs of its class (e. g. omeprazol or lansoprazole), pantoprazole reduces gastric acid secretion through inhibition of the portion on the gastric parietal cell. In combination with other drugs, pantoprazole can be used for the initial treatment of H. Pylori infection [1],... 

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. 

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]. 

Despite the success of several conunerdal benzimidazole proton pump inhibitors for the treatment of iflcer disease, work is still in progress to discover new benzimidazole-derived antiulcer drugs. Cinitapride (nil-related benzimidazole derivatives 122 have been prepared and studied for their antiulcerative activity [109]. hi addition, 1,3-disubstituted 3,4-dihydropyrimido[l,6-a]benzimidazoles and 3-substituted 3,4-dihydropyr-imido[l,6-a]benzimidazol-l(2H)-thiones exhibited good gastric antisecre-tory activity (> 50% inhibition) [110]. 

Prilosec, Rapinex, Zegerid) and its S-isomer, esomeprazole (Nexium), lansoprazole (Prevacid), rabeprazole (Aciphex), and pantoprazole (Protonix). These drugs have different substitutions on their pyridine and/or benzimidazole groups but are remarkably similar in their pharmacological properties. Omeprazole is a racemic mixture of R- and S-isomers the S-isomer, esomeprazole (S-omeprazole), is eliminated less rapidly than R-omeprazole, which theoretically provides a therapeutic advantage because of the increased half-life. Despite claims to the contrary, all proton-pump inhibitors have equivalent efficacy at comparable doses. 

Pantoprazole, a substituted benzimidazole sulphoxide, is a proton-pump inhibitor recommended for the treatment of acid-related GI diseases such as reflux esophagitis and duodenal and gastric ulcers (see also Figure 72). 

The pyridine ring is found in many current pharmaceuticals. It is present in some proton pump inhibitors used for reducing the amount of acid produced by the stomach. These dmgs can be used to treat reflux disease, ulcers, or heartburn. Omeprazole is sold by AstraZeneca Pharmaceuticals LP as the magnesium salt in the racemic form as PRILOSEC and as the S enantiomer as NEXIUM. Lansoprazole is sold by TAP Pharmaceuticals Inc. as PREVACID. Pantoprazole is sold by Wyeth Pharmaceuticals Inc. as the sodium salt under the name PROTONIX. Rabeprazole was developed by Eisai Co. Ltd., who sells it as the sodium salt under the name ACIPHEX. Each of these also contains a benzimidazole ring. 

Pantoprazole is a substituted benzimidazole sulfoxide proton pump inhibitor (Fig. 11). Like other proton pump inhibitors such as lansoprazole, all chiral benzimidazoles are administered as racemic mixtures. Pantoprazole is metabolized to pantoprazole sulphone as a major metabolite, and pantoprazole sulfide as a minor metabolite (Fig. 11). The reoxidation of pantoprazole sulfide to pantoprazole occurs in vivo, resulting in chiral inversion of pantoprazole enantiomers. Significant chiral inversion occurred after intravenous and oral administration of (-F)-pantoprazole [139]. The mechanism of this inversion has not yet been identified. 

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...

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