New Drug ClassesChiral switches
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drugs to be redeveloped and approved as single isomers to replace clinically established racemates were subsequently withdrawn.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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Dilevalol: a selective beta-2 adrenergic agonist vasodilator with beta adrenergic blocking activity
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Valvular heart disease associated with fenfluramine-phentermine
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