I thought the piece last week was responding to a specific enquiry from a student. The feedbacks showed that readers wanted more clarification. Chirality is an interesting aspect of drug development. The Australian Prescriber of Volume 27, 2 provides some basics. Have you ever tried putting your left shoe on your right foot or your right glove on your left hand? Your left and right hands and feet are non-superimposable mirror images of one another. Chemicals including drugs can behave in a similar way. Many drugs consist of a mixture of left- and right-handed molecules (enantiomers), but there is an increasing trend for the pharmaceutical industry to develop and market products containing only the left- or right-handed molecule.
Many single enantiomer drugs (suchas sertraline and salmeterol) are new chemical entities, others have been developed from currently marketed drugs which are a mixture of different enantiomers (racemates). An example is esomeprazole which is an enantiomer of the racemate omeprazole (and formed the basis of the discussion in the last piece). The term chiral switching has been coined to describe the development of single enantiomers from old racemate drugs.Enantiomer is one of a pair of stereoisomers that are non-superimposable mirror images of one another and therefore have a different 3-dimensional configuration. Isomers are compounds with the same molecular formula but with different 3-dimensional configuration. Racemate is a mixture of two enantiomers, usually in one-to-one ratio. Many drugs are marketed as racemates. They are said to be chiral drugs (from the Greek word for hand, cheir).
There are different methods for naming enantiomers. The definitive way is to use the prefix (R)- (right hand) and (S)- (left hand). Other prefixes are (+) and (–) or D and L. An example is ibuprofen which contains an equal amount of (R)-ibuprofen and (S)-ibuprofen.Enantiomers have identical physical and chemical properties such as molecular weight, solubility and melting point. The only difference is their three-dimensional spatial configuration.
Most drugs obtained from nature are chiral, but in nature only the biologically active enantiomer is synthesised. The poppy plant Papaver somniferum only synthesises the pain relieving (–) morphine. Morphine has a demanding chemical structure with five asymmetric centres. The technical difficulties and costs associated with chemically manufacturing large amounts for therapeutic use are such that it is better economically for companies to extract the morphine for the world market from poppies, rather than to artificially synthesise it. However, for many other chiral drugs, synthesis of the individual enantiomers is economically feasible.
The interactions in the body between a drug and the proteins (receptors, enzymes) which elicit therapeutic or adverse effects and eliminate the drug require a specific three-dimensional configuration of drug and protein. Since enantiomers have different three-dimensional configurations, the pharmacodynamics and pharmacokinetics of the two enantiomers which make up a racemic drug can be quite different. The differences often depend on whether the centre of asymmetry of the drug is in close proximity to the points of attachment to the protein. For example: (S)-ibuprofen is over 100-fold more potent an inhibitor of cyclo-oxygenase I than (R)-ibuprofen.(R)-methadone has a 20-fold higher affinity for the µ opioid receptor than (S)-methadone. (S)-citalopram is over 100-fold more potent an inhibitor of the serotonin reuptake transporter than (R)-citalopram.
The so-called inactive enantiomer (one that has much less affinity for the drug’s target site) may not be necessarily an inert substance. The cardiotoxicity of bupivacaine is mainly associated with the (R)-enantiomer. The psychomimetic effects of ketamine are more associated with the (R)-enantiomer. (S)-baclofen antagonises the effects of (R)-baclofen. Mefloquine is marketed as a racemate. (+)Mefloquine is more effective as malaria prophylaxis. (–)Mefloquine specifically binds to adenosine receptors in the central nervous system and accounts psychotropic effects of the drug.The beneficial effects of a drug can therefore reside in one enantiomer, with its paired enantiomer having no activity, some activity, antagonist activity against the active enantiomer, completely separate beneficial or adverse activity from the active enantiomer.
The distribution and elimination of drugs from the body also involves their interaction with proteins-the pharmacokinetics of enantiomers can also be different. The bioavailability of (R)-verapamil is more than double that of (S)-verapamil due to reduced hepatic first-pass metabolism. The clearance of (R)-fluoxetine is about four times greater than (S)-fluoxetine due to a higher rate of enzyme metabolism. The renal clearance of (R)-pindolol is 25% less than (S)-pindolol due to reduced renal tubular secretion. These pharmacokinetic properties can be modified in a stereoselective manner by disease, genetics, ethnicity, age and other drugs. The enantiomers of some drugs such as warfarin can be metabolised by different enzymes.
Chiral switching can therefore improve safety through increased receptor selectivity and potency, reduced adverse effects, longer or shorter duration of action (due to pharmacokinetic considerations-e.g. half-life). These can translate into a more appropriate dosing frequency decreased inter-individual variability in response commonly due to polymorphic metabolism and decreased potential for drug-drug interactions.
Some racemic drugs were patented without separate patents for each enantiomer. Pharmaceutical companies have seized the opportunity to develop and market or license single enantiomers of marketed chiral drugs. Omeprazole was the first proton pump inhibitor (PPI) for the management of peptic ulcer disease (PUD) and gastro-oesophageal reflux disease(GERD). It was a block-bluster in that it sold over $1 billion per year. There could therefore be commercially driven reason for chiral switches with the impending expiry of the patents of some ‘blockbuster’ racemic drugs. Manufacturers have developed and marketed the single enantiomer with a view to extending the patent franchise and protecting themselves from competitors who produce generic copies of the racemate. Esomeprazole, the (S)-enantiomer of omeprazole. All proton pump inhibitors exist as two inactive enantiomers (prodrugs) that are converted to active moieties which equally inactivate the H+/K+-ATPase pump. Both enantiomers of omeprazole are equipotent, however, their metabolism is different. (R)-omeprazole is mainly metabolised by the polymorphic CYP2C19 enzyme. There is a 7.5-fold difference in the systemic exposure to (R)-omeprazole in patients who are poor metabolisers compared to extensive metabolisers. With (S)-omeprazole this difference is reduced to about three-fold so it was argued that use of esomeprazole would be associated with less inter-individual variability in efficacy.
Not all chiral switches have been beneficial. Thee clinical development of (R)-fluoxetine for depression was stopped because of a small but statistically significant prolongation of the QT interval with high doses. Dilevalol was thought to have advantages over labetalol, but was removed from the Japanese market because of hepatotoxicity.
Drug development is becoming longer and more complex, while marketing is increasingly competitive with chiral switching being seen as a key strategy. This should still be supported by solid clinical evidence to guarantee patient safety.
EDWARD O. AMPORFUL