Racemic drugs are not necessarily less efficacious and less safe than their single-enantiomer components

Abstract

Practitioners of drug discovery and development of chiral drugs are confronted with the dilemma whether to develop a racemate or a single enantiomer. In 2024, articles were published stating that single enantiomers are clinically more potent than racemic mixtures and that the use of single enantiomers instead of racemates improves the effectiveness and/or safety of treatment. The Commentary provides a rebuttal of these allegations. A historical survey of the motivation for developing single-enantiomer drugs is given. Cases of preference of racemate/diastereomeric-mixture drugs over single-enantiomer drugs are described, along with the following cases of teaching away from chiral switches of racemate/diastereomeric-mixture drugs to single-enantiomer drugs: rapid interconversion in vivo of paired enantiomers, fast in vivo conversion of a diastereomeric-mixture drug to its active form, enantiomerization in vivo of an (R)-enantiomer to its paired (S)-enantiomer. Advantages of racemic drugs versus single-enantiomer drugs and vice versa are listed. Racemate/diastereomeric-mixture drugs are not necessarily less efficacious and less safe than their single-enantiomer components. They will continue to serve as potential candidates for chiral switches. The Commentary concludes with highlighting the proposition that development of chiral drugs should proceed forward with the racemate until and unless some relevant differentiated property is identified.