Enantiomers, racemates, and the chiral switch

There was recently a flutter in the case between Sanofi and generics involving the optically-active PLAVIX ((S)-clopidogrel).

To date, one of the more interesting situations involving a "chiral switch" to an optically-active enantiomer from an optically-inactive racemate is that of Nexium (enantiomer) and Prilosec (racemate, omeprazole). The history of that switch is interesting. Initial tests showed that the R enantiomer of omeprazole was significantly more active than the S enantiomer or the racemate in the rat, justifying clinical trials. One of the scientists observed: "We were lucky to test in rats. Later tests showed that the enantiomers have equal activity in dogs. IF we had tested in DOGS to start with, we wouldn't have continued." Results of HUMAN testing of both enantiomers were DIFFERENT than in rats or dogs: the S enantiomer is more active. Thus did (S)-omeprazole find itself vying with three omeprazole derivatives from the medicinal chemistry effort for the title "improved omeprazole." Esomeprazole (Nexium) won.

A review by John Caldwell of the University of Liverpool and organic chemists Israel Agranat and Hava Caner at the Hebrew University of Jerusalem indicates that since 1990, the proportion of single-enantiomer drugs among approved new chemical entities worldwide has been consistently greater than that of racemates [Nat. Rev. Drug Discovery, 1, 753 (2002)]. Chiral effects in pharmaceuticals are being exploited in several ways: by developing better single-enantiomer versions of already approved racemic drugs, [chiral switching], by discovering distinct therapeutic uses for enantiomers of chiral drugs, and by creating non-racemic mixtures of enantiomers.

Another interesting case is that of Citalopram (racemate, Celexa) and escitalopram (enantiomer, Lexapro). Also, see U.S. Patents 5,114,714 and 5,114,715. The '714 claims that using the R enantiomers of the anesthetics isoflurane and desflurane is better than using the racemate. The '715 claims that using the S enantiomers of the same anesthetics is better than using the racemate. Also, expect to see something along the lines of dextromethorphan on one of television's crime investigation (CSI) or medical shows: one enantiomer (dextromethorphan) is a cough medicine and the other enantiomer (levomethorphan) is a powerful narcotic. If one does only a routine chemical analysis (eg, gas chromatography, GC), one can't tell the difference.

In the future, also contemplate Provigil (racemate) and Nuvigil (enantiomer).