New Single-Isomer Compounds on the Horizon

In 1992, the Food and Drug Administration (FDA) issued new guidelines governing stereoisomerism in new-drug development. The guidelines strongly encourage the development of single isomers and discourage stereoisomeric (eg, racemic) mixtures. As a result, most new chiral drugs are being developed as single enantiomers (ie, single isomers). There are three mechanisms for the identification and development of new single-isomer drugs: chiral switches (CS), chiral metashifts (CM), and new single-isomer chemical entities (NSICEs). In a CS, one of the two enantiomers of an established racemate is developed as a new drug, with the expectation that the single-isomer form has advantages over the racemic parent in terms of efficacy and/or adverse effects. Many new CS drugs are in development, eg, (S)-oxybutynin for urinary incontinence and escitalopram for depression. In a CM, a chiral metabolite of a drug is developed, in single-isomer form, as an agent with advantages over the parent. Among the current CM drugs in development are (+)-norcisapride (safer GI prokinetic agent than the racemic parent cisapride) and (S)-desmethylzopiclone (antianxiety agent, metabolite of the sedative-hypnotic zopiclone). Many NSICEs are in development, eg, rosuvastatin as an antihypercholesterolemic, posaconazole as an antifungal, sitafloxacin as a fluoroquinolone antibacterial, pregabalin as an anticonvulsant, abarelix as an antineoplastic, etc. As in the development of any new drug, not every single-isomer candidate will reach the clinic, but there is no doubt that the move to single-isomer agents is an important step forward in the search for better and safer drugs.