Addition to “The Death of the Strategy of Classical Chiral Switches Is an Exaggeration”

Additional text should be included following the Conclusion section as a Note Added after Issue Publication: According to this Viewpoint, the strategy of classical chiral switches of drugs and the development of racemic drugs which might later serve as candidates for chiral switches are alive. This message has since been challenged. Senkuttuvan et al. published in RSC Advances in October 2024 a mini-review entitled “The significance of chirality in contemporary drug discovery−a mini review”, concluding: “Over the last ten years, the traditional chiral swap method has vanished.”¹ It should be noted, however, that the classical chiral switch levamlodipine maleate, indicated for the treatment of hypertension, was approved by the FDA in December 2019 (as indicated in our Viewpoint). Our Viewpoint highlighted the relevance and importance of the strategy of chiral switches, not only as a component of the strategy of drug repurposing/chiral-switches combination.² We point out here additional sources for potential chiral switches. In this context, it is noted that up to 2022, the following five Class 3 (aka Class III) atropisomeric drugs were approved by drug regulatory authorities globally:³ (i) telenzepine, a racemate: (aS)-enantiomer and (aR)-enantiomer (axial chirality), (M)-enantiomer and (P)-enantiomer (helicity);^4,5 (ii) colchicine, a 99:1 mixture of (−)-(aS,7S)- and (+)-(aR,7S)- diastereomers;^6,7 (iii) lesinurad, a racemate (discontinued in 2019);⁸ (iv) sotorasib, the single (1M, 2S) enantiomer;⁹ and (v) esaxerenone, the single (−)-(aS)-enantiomer¹⁰ (Figure 1). Telenzepine showed marked enantioselectivity in pharmacological activity: (+)-telenzepine is markedly more active than (−)-telenzepine, but the absolute configuration of the more active enantiomer has not been reported.⁵ Racemic and diastereomeric mixtures of approved Class 3 atropisomeric drugs should also be considered as potential candidates for chiral switches. Telenzepine would be especially suitable for a chiral switch. (Figure presented) The very recently published 2024 Medicinal Chemistry Reviews contains a chapter entitled “New Chemical Entities Entering Phase III Trials in 2023”, reporting 39 NCEs, including the chiral drugs leriglitazone and olgotrelvir.¹¹ At first thought, these two drugs may be considered potential candidates for chiral switches. Leriglitazone is a mixture of four stereoisomers, two pairs of enantiomers, (R,R/S,S) and (R,S/ S,R) (namely, two racemates) (Figure 2). The European Medicines Agency (EMA) declined on May 24, 2024, the approval of leriglitazone (Nezglyal). The EMA’s Committee for Medicinal Products for Human Use recommended that the overall benefit/risk balance of Nezglyal is negative, concluding that “the application does not meet the requirements for conditional marketing authorisation.”¹² The proposed indication of leriglitazone was for the treatment of pediatric and adult male adrenoleukodystrophy (ALD) patients aged 2 years and older with cerebral adrenoleukodystrophy (cALD). Leriglitazone is an active metabolite of pioglitazone hydrochloride, FDA NDA#021073, approved on July 15, 1999 (Figure 2), a racemic drug indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus in multiple clinical settings.¹³ The two enantiomers of pioglitazone interconvert in vivo. No differences were found in the pharmacological activity between the two enantiomers.¹³ “Leriglitazone has [blood-brain barrier] penetrating properties and the capability to elicit a [central nervous system] effect − Pioglitazone does not.”¹² The strategy of deuterium-enabled chiral switches of racemic drugs has been applied to pioglitazone: deuterated (R)-pioglitazone (PXL065) is undergoing clinical development for the treatment of nonalcoholic steatohepatitis.^14,15 We propose here to consider applying the chiral-switch strategy to leriglitazone by developing one of its pairs of diastereomeric mixtures, RS,R or RS,S, and/or their deuterated (R,R)- or (R,S)-enantiomers. Olgotrelvir is a mixture of two epimers, (R,S,S,S) and (S,S,S,S) (Figure 2). In contrast to leriglitazone, olgotrelvir is converted in biorelevant media and human blood to its active form AC1115 (Figure 2), a single enantiomer (S,S,S) aldehyde, thus losing one of its chiral centers. Under these circumstances, a chiral switch of olgotrelvir to one of its epimers would be useless. Olgotrelvir was designed as a next-generation antiviral targeting the SARS-CoV-2 main protease, an essential enzyme for SARS-CoV-2 replication.¹⁶ (Figure presented). In conclusion, we call here to continue considering the application of the chiral-switch strategy to approved racemic and diastereomeric-mixture drugs, when applicable, including approved atropisomeric drugs.