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Geminal Diheteroatomic Motifs: Some Applications of Acetals, Ketals, and Their Sulfur and Nitrogen Homologues in Medicinal Chemistry and Drug Design
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    Geminal Diheteroatomic Motifs: Some Applications of Acetals, Ketals, and Their Sulfur and Nitrogen Homologues in Medicinal Chemistry and Drug Design
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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2021, 64, 14, 9786–9874
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    https://doi.org/10.1021/acs.jmedchem.1c00790
    Published July 2, 2021
    Copyright © 2021 American Chemical Society

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    Acetals and ketals and their nitrogen and sulfur homologues are often considered to be unconventional and potentially problematic scaffolding elements or pharmacophores for the design of orally bioavailable drugs. This opinion is largely a function of the perception that such motifs might be chemically unstable under the acidic conditions of the stomach and upper gastrointestinal tract. However, even simple acetals and ketals, including acyclic molecules, can be sufficiently robust under acidic conditions to be fashioned into orally bioavailable drugs, and these structural elements are embedded in many effective therapeutic agents. The chemical stability of molecules incorporating geminal diheteroatomic motifs can be modulated by physicochemical design principles that include the judicious deployment of proximal electron-withdrawing substituents and conformational restriction. In this Perspective, we exemplify geminal diheteroatomic motifs that have been utilized in the discovery of orally bioavailable drugs or drug candidates against the backdrop of understanding their potential for chemical lability.

    Copyright © 2021 American Chemical Society

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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2021, 64, 14, 9786–9874
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.jmedchem.1c00790
    Published July 2, 2021
    Copyright © 2021 American Chemical Society

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