Consecutive double chiral-switches strategy. ADHD methylphenidate drugs: from two racemates via racemate to enantiomer

The <i>Perspective</i> presents the strategy of double chiral switches of drugs, illustrating the scenario of consecutive double chiral switches of methylphenidate. The two chirality centers of methylphenidate hydrochloride give rise to four stereoisomers grouped into two racemates, two enantiomer pairs: [(α<i>R</i>,2<i>S</i>)/(α<i>S</i>,2<i>R</i>)] (racemate a) and [(α<i>R</i>,2<i>R</i>)/(α<i>S</i>,2<i>S</i>)] (racemate b). A detailed analysis of the development, drug-regulatory approvals and the corresponding patents and trademarks of methylphenidate drugs indicated the following double chiral switches: (±)-[(α<i>R</i>,2<i>R</i>)/(α<i>S</i>,2<i>S</i>)]-methylphenidate HCl + (±)-[(α<i>R,2S</i>)/(α<i>S</i>,2<i>R</i>)]-methylphenidate HCl (Centedrin)→(±)-[(α<i>R</i>,2<i>R</i>)/(α<i>S</i>,2<i>S</i>)]-methylphenidate HCl (Ritalin)→(+)-(α<i>R</i>,2<i>R</i>)-methylphenidate HCl (Focalin). The analysis showed that the Food and Drug Administration approval of Ritalin in 1955 represented the first chiral switch of the mixture of two racemates to the single racemate b. In 2001, Ritalin underwent a second chiral switch to the single-enantiomer Focalin. Ritalin and Focalin developed into successful Attention-Deficit/Hyperactivity Disorder (ADHD) drugs. Notably, the single-enantiomer drug Focalin has not driven away the racemate Ritalin from ADHD markets. The notations of the active ingredients of Ritalin (methylphenidate hydrochloride) and of Focalin (dexmethylphenidate hydrochloride) are stereochemically flawed and the designations of the stereodescriptors of relative configurations <i>erythro</i> and <i>threo</i> are obsolete. The <i>Perspective</i> calls for correct notations of methylphenidate drugs and for future applications of the double chiral-switches strategy.