Racemic switch

Due to their almost identical chemical structure, enantiomers represent a subtle class of analogues. Often in a pair of enantiomers, the desired biological activity is concentrated in only one enantiomer. Then, the passage from a racemic mixture to the pure active eutomer - which is usually termed racemic switch - can produce an improved drug. However, in some cases and despite their similar constitution, both enantiomers can have totally different pharmacodynamic or pharmacokinetic profiles. 

A general trend in the pharmaceutical industry is to switch from racemates to single enantiomers. Examples are given by (i )-(-)-verapamil, (S)-fluoxetin, (S)-keto-profen, (R)-albuterol, levofloxacin, esomeprazole (see Chapter II-2), levocetirizine, and many others [17,18]. In addition to the quality improvement of the drug, this switch represents also a way to prolong its life insofar that the isolated eutomer is legally considered as a new drug entity. 

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Pharmaceuticals and intermediates represent another important class of compounds. General classes of drugs that may well lend themselves to the IBC technology include the chiral non-steroidal anti-inflammatory profen drugs, norephedryns, and intermediates for a number of important drug classes including (i-blockers and racemic switch candidates. 

The area of racemic switches where a single enantiomer is developed subsequently to a corresponding racemate which is already on the market has attracted much interest [7, 8]. A description of the preclinical and clinical development of dexketoprofen provides a detailed example of one of these racemic switches [21]. The regulations in Europe and the US both allow for the development of a single enantiomer from a racemate by the use of bridging studies between the old and new applications. One problem to be considered is how a company which was not responsible for the original development can provide equivalent data. 

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... 

The recently launched Esomeprazole (97, AstraZeneca), which is the (5)-isomer of the anti-ulcer drug. Omeprazole (a typical racemic switch agent) is effectively synthesized by employing diethyl tartrate (DET), titanium tetraisopropoxide, and cumene hydroperoxide with > 90 % yield and > 90 % ee (Scheme 29) [89]. Under optimal conditions an amazing cost performance is realized to produce Esomeprazole cheaper than the racemic Omeprazole [89b]. 

New commercial opportunities for racemic switching a drug previously marketed as a racemate can be redeveloped and introduced as an enantiomeri-cally pure form, possibly useful for extending patent protection of a key product. 

As for the so-called racemic switches , i.e., chiral drugs that are produced and marketed as racemic mixtures and for which conversion to the pure enantiomer can be envisaged, the scenario is slightly different. In this case, a stereoselective approach can be considered more useful than a resolution step (especially if this is combined with a racemization of the undesired isomer and by its recycling), only if the stereoselective process connects well with the existing synthetic procedure or effectively reduces the time and cost of production. 

In the pharmaceutical industry, chirality issues are causing particular problems in the development of new chemical entities but also opportunities for the so called "racemic switch" when an established racemate product approaches patent expiry. 

The distomer counteracts the eutomer Racemic switches The distomer is metabolized to unwanted or toxic products Deletion of the chiral centre Usefulness of racemic mixtures... 

Midha, K.M. McKay, G. Rawson, M.J. Hubbard, J.W. The impact of stereoisomerism in bioequivalence studies. J. Pharm. Sci. 1998, 87, 797-802. Stinson, S. Counting on chiral drugs. Chem. Eng. News 1998, 76, 83-103. DiCicco, R. The future of S-(-f)-ibuprofen and other racemic switches. In ChiroT 93 USA Spring Innovations Stockport, UK, 1993. 

Because patent expiry for a racemate tends to proliferate the drug as generics, product line extension for an existing racemate technology can be obtained by switching to a single stereoisomeric form (the racemic switch). This is an incentive to produce the drugs in their pure enantiomeric forms. 

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