Proton pump inhibitors enantiomers

Enzymes often prove to be the catalyst of choice for numerous transformations, and their prowess is particularly noteworthy for the synthesis of chiral molecules. The ability of biocatalysts to impart chirality through conversion of prochiral molecules or by transformation of only one stereoisomer of a racemic mixture stems from the inherent chirality of enzymes. As noted in the introduction to this book (Chapter 1), the chiral drug market is increasing, partly as a result of the need to produce single enantiomers as advocated by the U.S. Food and Drag Administration.1 The ability to extend the patent life of a drug through a racemic switch also plays a role in this increase. An example of a racemic switch is Astra Zeneca s Esomeprazole, a proton pump inhibitor (see Chapter 31).2... 

AstraZeneca (formerly Astra) has launched the proton-pump inhibitor esomeprazole (19) (as Nexium) as a treatment for peptic ulcer, gastroesophageal reflux disease, duodenal ulcer, and esophagitis. Esomeprazole is the (S)-enantiomer of omeprazole and was developed as a result of its improved pharmokinetic profile and better potency after oral dosing than (f )-form of omeprazole or the racemate. The dosage is higher than would be expected for a simple chiral switch. The stereogenic center is at sulfur. Detailed accounts of the development of the process have been published.189190... 

Esomeprazole 26 Gastric proton pump (inhibitor) Analog of omeprazole (S)-Enantiomer of omeprazole, which is racemic Enhanced oral bioavailability Esophagitis GI tract... 

Different proton pump inhibitors depend differently on CYP2C19 for oxidative metabolism, and the enantiomers show variation in dependenoe on CYP2C19 and other pathways (principally CYP3A4). Pantoprazole and lansoprazole show greater metabolism via CYP2C19, with the enantiomers being affected differently, than rabeprazole, which is metabolized only to a small extent by oxidative CYP450 enzymes. 

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

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. 

Omeprazole (Prilosec, 21), the first H /K -ATPase inhibitor, also known as a proton pump inhibitor (PPI), was marketed as a treatment for gastric ulcers since 1988. It functions by preventing acid production in the mucosa. Omeprazole was the best-selling drug for several years until its patent expiration in 2001, at which time, esomeprazole (Nexium, 22), tihe (S)-enantiomer of racemic omeprazole (21), was launched. The mechanism of... 

There are many synthetic techniques for stereoselective synthesis and because of the importance much research is currently devoted to expanding these techniques. Omeprazole, marketed as Prilosec , was the first proton pump inhibitor and is used as a treatment for gastric ulcers. It is a racemic mixture. The S enantiomer has better pharmacokinetics and pharmacodynamics than the racemic mixture and therefore higher efficacy in controlling acid secretion [38]. The S enantiomer is called esomeprazole and is marketed as Nexium . Nexium has annual sales of 8.4 billion [39]. The chiral center is at the sulfur and the enantiomers can be separated by derivatizing with a R-(-) mandelic acid chiral auxiliary to form two diastereomers. Unlike enantiomers, diastereomers have different physical properties. The diastereomers can be separated by HPLC and then the chiral auxiliary removed to afford each of the omeprazole enantiomers. Alternatively, the sulfide precursor can be asymmetrically oxidized to form esomeprazole in 99.99% enantiomeric excess (ee) [40]. Enantiomeric excess means the excess amount of one enantiomer over the racemic mixture. If something is 80% ee that means that 20% is a racemic mixture and the other 80% is excess of that enantiomer. In this example, for 100 g, there are 90 g of the predominant enantiomer and 10 g of the lesser enantiomer in other words, 20 g is a racemic mix (lOg of each enantiomer) and 80g is excess enantiomer. 

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