The Quest for Secondary Pharmaceuticals: Drug Repurposing/Chiral-Switches Combination Strategy

Abstract

Drug repurposing toward new medical uses and chiral switches are elements of secondary pharmaceuticals. The drug repurposing and chiral-switches strategies have mostly been applied independently in drug discovery. Drug repurposing has peaked in the search for therapeutic treatments of the Coronavirus Disease 2019 pandemic, whereas chiral switches have been overlooked. The current Perspective introduces the drug repurposing/chiral-switches combination strategy, overviewing representative cases of chiral drugs that have undergone this combination: ketamine, flurbiprofen, fenfluramine, and milnacipran. The deuterium-enabled chiral switches of racemic thalidomide analogs, a variation of the repurposing/chiral-switch combination strategy, is also included. Patenting and regulatory-exclusivity considerations of the combination strategy in the discovery of new medical uses are considered. The proposed combination creates a new synergy of its two elements, overcoming arguments against chiral switches, with better prospects for validation of patents and regulatory exclusivities. The combination strategy may be applied to chiral switches to paired enantiomers. Repurposing/chiral-switch drugs may be ‘obvious-to-try’; however, their inventions may be unexpected and their patents nonobvious. Patenting repurposing/chiral-switch combination drugs is not ‘evergreening’, ‘product hopping’, and ‘me-too’. The expected benefits and opportunities of the combined repurposing/chiral-switch strategy vis-à-vis its two elements are superior pharmacological properties, overcoming arguments against patent validities, challenges of chiral-switch patents, reduced expenses, shortened approval procedures, and higher expectations of regulatory exclusivities.

Chirality of New Drug Approvals (2013–2022): Trends and Perspectives

“…We were further interested in assessing trends in the practice of chiral switching. Table lists new active substances approved by the FDA and EMA that have arisen from a chiral switch strategy between 1976 and 2022 compiled from refs , , , , and . In the ten years from 2013 to 2022, no NASs approved by the EMA were identified as chiral switches.…”

“…Ketamine has been marketed as a general anesthetic under the brand name Ketalar in the US since it was granted approval by the FDA in 1970 . It is widely used as a general anesthetic and is included on the World Health Organisation (WHO) List of Essential Medicines for this use.…”

“…Both were withdrawn by the FDA in 1990s due to evidence of cardiotoxicity, resulting in valvular heart disease . Finlepta, containing racemic fenfluramine, is a treatment for seizures associated with Dravet syndrome that was approved by the FDA and EMA in 2020 . Finlepta is therefore a result of drug repurposing and a chiral switch back to the racemate.…”

“…This strategy is of particular importance in the search for drugs to treat rare diseases where there is less incentive for companies to invest in drug discovery and development. The benefits of combining chiral switch and drug repurposing strategies include improved drug safety and/or efficacy, reduced development expenses, faster approval time, higher likelihood of a marketing exclusivity period, and patentability …”

Stereoselective Inhibition of High- and Low-Affinity Organic Cation Transporters

“…On the other hand, chiral switching was not always successful. Exemplarily, ( R )-fluoxetine, ( S )-fenfluramine, and ( S )-sotalol had a worse outcome in clinical studies. − The underlying mechanisms, not in all instances well understood, may rely on different off-target effects of the enantiomers; for instance, ( S )-sotalol has none of the possibly beneficial beta-receptor blocking activity.…”