Chiral switch

[1][2] The term chiral switching was introduced by Agranat and Caner in 1999[3] to describe the development of single enantiomers from racemate drugs.

[5] To express the pharmacological activities of each of the chiral twins of a racemic drug two technical terms have been coined eutomer and distomer.

A positive consequence of this redesigning approach is that it has given a new life to an old drug, minimizing or avoiding the undesirable side-effect profile.

A pragmatic solution could be in favor of a decision-tree approach, incorporating various factors such as pharmacodynamic, pharmacokinetic, toxicological profile of the enantiomers, enantiomer-enantiomer interaction potential, safety, efficacy, risk-benefit ratio, chiral inversion, distomer liability, physicochemical properties, cost of separation and production, quality control criteria, marketing edge, etc.

For instance, thalidomide, the sedative drug, undergoes bidirectional chiral inversion or racemization in biological systems.

[24][25][26][27] When a sponsor/innovator seeks to develop a single enantiomer from a racemic drug, the regulatory agencies demand them to conduct bridging studies.

The intent of the bridging studies is to make sure that the companies are not scarifying some protective effect conferred by the other" isomer when they develop a chiral drug as single enantiomer rather than a racemate.

The table below enumerates couple of chiral switches aborted or withdrawn due stereochemically engineered toxicity.

[41] Some chiral switches are performed to re-start the patent clock for a medication without reducing side effects or improving efficacy.

The purpose of the switching is to develop an active metabolite which will be devoid of the side-effects and have an improved therapeutic profile compared to the parent chiral drug.

Some examples of chiral drug to metabolite switches,[22] (those in the market and others under investigation) include terfenadine to fexofenadine, halofantrine to desbutylhalofantrine, and cisapride to norcisapride.

The combination strategy may improve pharmacology, patents, reduce costs, speed up approval times, and increase regulatory exclusivities.

The benefits of the combination strategy include superior pharmacology, stronger patents, shorter approval times, and more exclusivity.

This perspective calls for a comprehensive search for worldwide-approved racemic drugs to be repurposed and combined with chiral switches.