Differentiation of antiinflammatory and antitumorigenic properties of stabilized enantiomers of thalidomide analogs

Proceedings of the National Academy of Sciences of the United States of America
Vincent JacquesSheila H DeWitt

Abstract

Therapeutics developed and sold as racemates can exhibit a limited therapeutic index because of side effects resulting from the undesired enantiomer (distomer) and/or its metabolites, which at times, forces researchers to abandon valuable scaffolds. Therefore, most chiral drugs are developed as single enantiomers. Unfortunately, the development of some chirally pure drug molecules is hampered by rapid in vivo racemization. The class of compounds known as immunomodulatory drugs derived from thalidomide is developed and sold as racemates because of racemization at the chiral center of the 3-aminoglutarimide moiety. Herein, we show that replacement of the exchangeable hydrogen at the chiral center with deuterium allows the stabilization and testing of individual enantiomers for two thalidomide analogs, including CC-122, a compound currently in human clinical trials for hematological cancers and solid tumors. Using "deuterium-enabled chiral switching" (DECS), in vitro antiinflammatory differences of up to 20-fold are observed between the deuterium-stabilized enantiomers. In vivo, the exposure is dramatically increased for each enantiomer while they retain similar pharmacokinetics. Furthermore, the single deuterated enantiomers rela...Continue Reading

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Citations

Feb 5, 2016·Proceedings of the National Academy of Sciences of the United States of America·Sergio Martínez CuestaJanet M Thornton
Jul 20, 2016·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Rutika R NaikSharmila A Bapat
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Jan 31, 2018·Future Medicinal Chemistry·Sean T Toenjes, Jeffrey L Gustafson
Aug 9, 2018·Future Medicinal Chemistry·Krzysztof Z Łączkowski, Angelika Baranowska-Łączkowska
Sep 21, 2019·Future Medicinal Chemistry·Sarah CargninTracey Pirali
Apr 14, 2021·Angewandte Chemie·Quentin DherbassyDavid J Procter
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Oct 17, 2020·ACS Medicinal Chemistry Letters·Sheila DeWittVincent Jacques

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