Deuterated Drug Molecules: Focus on FDA-Approved Deutetrabenazine

Sheila H. DeWitt† and Bruce E. Maryanoff*,‡,§ †DeuteRx LLC, 300 Brickstone Square, Suite 201, Andover, Massachusetts 01810, United States ‡Baruch S. Blumberg Institute, 3805 Old Easton Road, Doylestown, Pennsylvania 18902, United States Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States F the longest time, researchers have sought to use deuterium in place of hydrogen in drug molecules to inhibit metabolic conversion to less active or inactive molecules or to stabilize stereogenic centers to stereomutation in enantiomers and diastereomers. The basic idea here is to prolong the residence time of the active drug species in plasma to achieve greater efficacy and/or to avoid adverse side effects. While such deuteration approaches make eminent sense in principle, several decades have slipped by without any key products being approved by the U.S. Food and Drug Administration (FDA) to validate the expected material advantage in the pharmaceutical marketplace. Now, this situation has clearly changed with the FDA granting marketing approval for the first deuterated drug molecule, deutetrabenazine (1; a racemic mixture), which is useful in treating chorea (an involuntary movement disorder) associated with Huntington’s disease and tardive dyskinesia. Deutetrabenazine is an analogue of the old drug tetrabenazine (2), with the two methoxy groups in the latter being replaced by a pair of trideuteromethoxy groups, thereby altering the rate of metabolism to afford greater tolerability and an improved dosing regimen.