Separation of the preferred enantiomer from racemic drugs, i.e., chiral switching,” often improves efficacy and reduces toxicity. However, this strategy is not applicable for all chiral compounds particularly for molecules with hydrogen-containing chiral centers, which can be prone to rapid enantiomerization. Deuterium incorporation can stabilize such chiral centers while retaining the pharmacologic characteristics of the parent racemic mixture, thereby enabling their chiral switch. We discovered “deuterium-enabled chiral switching” (DECS) as a means of improving on the therapeutic promise of racemic drugs and have demonstrated its utility with the isolation and characterization of stable preferred enantiomers. During our studies of interconverting racemic compounds with a hydrogen-containing stereocenter alpha to a carbonyl, we learned that the effect of deuteration on enantiomerization is unpredictable and highly variable. Below are highlights of the effects observed with several racemic compounds including pioglitazone, mitoglitazone, inolitazone, prasugrel, donepezil, lenalidomide, avadomide, iberdomide, and bupropion. Stabilization with deuterium may vary: - by compound even within the same compound class (e.g., thiazolidinediones); and - as a function of stereochemistry (sometimes there is no stabilization for one of the enantiomers). To date, the effects observed when deuterium is used to stabilize enantiomers include: 1. Reduced rates of enantiomerization between 0-35x for various deuterated compounds. 2. Reduced rates of degradation – in addition to reduced enantiomerization (e.g., degradation of thalidomide analogs varies from none to 4x). 3. Different rates of D/H exchange (none - 2.5x) between deuterated enantiomers of the same compound. 4. Stereoselective formation of one protonated enantiomer versus the other due to different reaction kinetics (e.g. d-R forms predominately h-R vs h-S). 5. Sometimes limited predictive value for in vivo effects of in vitro D/H exchange and enantiomerization studies.

Surprising discoveries while using deuterium to stabilize enantiomers for chiral switching

ACS Spring 2022

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