The strategy of chiral switches in drug discovery

The chirality of drugs has become a major theme in the design, discovery, development, patenting and marketing of new drugs1. There are two principal scenarios in chiral drug development: the de novo development of an enantiomerically pure drug, or a switch from an existing racemic drug to one of its enantiomers1,2. For many years, the pharmacopoeias were dominated by racemates. This trend was inverted in the mid-1980s: most of the chiral new molecular entity (NME) drugs were developed and marketed as single enantiomers. A chiral switch is the development of a single enantiomer from a chiral drug that has been developed (and often approved and marketed) previously as a racemate or as a mixture of diastereomers. The essential criterion of a chiral switch is a change in the status of chirality3. A list of chiral drugs that have successfully undergone a chiral switch will be presented, together with considerations on patentability and regulatory exclusivities of chiral-switch drugs. A special focus will be given to the antimalarial racemic drugs chloroquine (CQ) phosphate and hydroxychloroquine (HCQ) sulphate4 (Figure 1) which were repurposed for hospitalized patients affected by COVID-19 under an Emergency Use Authorization (EUA) by FDA in 2020 (later withdrawn). We called for adopting a variant of the repurposing strategy by developing the more-promising single enantiomers (S)-CQ and/or (S)-HCQ for the cure of COVID-19. Finally, deuterium-enabled chiral switches (DECS)5 of teratogenic racemic thalidomide and analogs which undergo racemization in vivo will be analyzed, in light of the finding that deuteration can stabilize hydrogen-containing chiral centers.