Elsevier

The Lancet

Volume 355, Issue 9209, 25 March 2000, Pages 1085-1087
The Lancet

New Drug Classes
Chiral switches

https://doi.org/10.1016/S0140-6736(00)02047-XGet rights and content

Summary

Developments in synthetic and analytical chemistry have provided the tools to differentiate between two enantiomers (mirror images) of drugs or between the parent compound and metabolite(s) with respect to desired and undesired pharmacological effects. Several drugs are now marketed or being developed as single enantiomers in place of a previous racemic mixture, a process known as “chiral switching”. It is easier to understand “pure” as opposed to “mixture” pharmacology but whether the promise of chiral (and metabolite) switches will translate into real clinical advances remains to be seen.

Section snippets

Chiral switching

The potential advantages of chiral switching include an improved therapeutic index through increased potency and selectivity and decreased side-effects; an improved onset and duration of effect; and a decreased propensity for drug-drug interactions, mediated largely by exploitation of stereoselectivity in pharmacokinetic properties.

A powerful stimulus for chiral switching is the fact that many blockbuster drugs have been developed and licensed as racemates (eg, fluoxetine, omeprazole), and

Failures

Unfortunately, the first two drugs to be redeveloped and approved as single isomers to replace clinically established racemates were subsequently withdrawn. Dilevalol, a partial β2-agonist, is one of the four isomers (R,R) of labetalol, a combined α and β blocker. While dilevalol had the advantage of not producing postural hypotension, it never reached the market owing to hepatoxicity not seen to the same extent with labetalol.5 The anorectic effect of racemic fenfluramine is due largely to the

Recently licensed

In 1979 seven cases of presumed inadvertent intravenous injection of racemic bupivacaine and etidocaine resulting in sudden cardiovascular collapse with difficult resuscitation or death were reported.7 This prompted a re-evaluation of the systemic safety of the longer-acting amide local anaesthetics, indicating that in vitro and in animals the (S)-isomers are significantly less cardiotoxic than their antipodes and the racemate. Consequently, the single (S)-forms of ropivacaine (the propyl

In the pipeline

Examples of single enantiomers at various stages of development are shown in panel 1. Of particular note are the two isomers of fluoxetine and perprazole, the (S)-form of omeprazole.

Amongst the selective serotonin-reuptake inhibitors, fluoxetine and citalopram are available as racemates; with sertaline and paroxetine, only the enantiomer with the more potent serotoninergic activity is marketed as an antidepressant; fluvoxamine is achiral. Steric aspects of the pharmacology of fluoxetine are

Drug to metabolite

The principle of switching from a racemate to an active isomer can be extended to replacement of a drug with an active metabolite and, ideally, the more active isomer of that metabolite. A recent, enforced, example of such a switch is the substitution of terfenadine with its active metabolite fexofenadine, which retains the antihistaminic activity of the parent drug but is virtually devoid of cardiac side-effects.15 Other drugs under investigation for the possibility of “metabolite switching”

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