The market of chiral drugs: Chiral switches versus de novo enantiomerically pure compounds

This review article is aimed at providing an overview of the current market of chiral drugs by exploring which is the nowadays tendency, for the pharmaceutical industry, either to exploit the chiral switching practice from already marketed racemates or to develop de novo enantiomerically pure compounds. A concise illustration of the main techniques developed to assess the absolute configuration (AC) and enantiomeric purity of chiral drugs has been given, where greater emphasis was placed on the contribution of enantioselective chromatography (HPLC, SFC and UHPC). Afterwards, we focused our study on the cohort of 45 new drugs that have been approved by the US Food and Drug Administration (FDA) in 2015. We extracted the chemical structure of the new drugs from the FDA approval chemistry reviews available on the database of the agency's Center for Drug Evaluation and Research (CDER), and we selected a subgroup (i.e., 44% of the cohort) of small-molecule active pharmaceutical ingredients (APIs) containing one or more chirality centers. On the basis of the FDA dossiers examined, it emerged that all the chiral drugs approved by the FDA in 2015 are enantiomerically pure compounds with a well-defined AC, with the exception of one, namely lesinurad, which has been licensed as the racemate of two enantiomeric atropoisomers, arising because of the hindered rotation around the single C-N bond in the naphthalene ring. Finally, none of the previously developed racemates has been switched to the single-enantiomer version in 2015. (C) 2017 Elsevier B.V. All rights reserved.