Geminal Diheteroatomic Motifs: Some Applications of Acetals, Ketals, and Their Sulfur and Nitrogen Homologues in Medicinal Chemistry and Drug DesignClick to copy article linkArticle link copied!
- Yong-Jin Wu*Yong-Jin Wu*Phone: (617) 494-7410. Email: [email protected]Small Molecule Drug Discovery, Bristol Myers Squibb Research and Early Development, 100 Binney Street, Cambridge, Massachusetts 02142, United StatesMore by Yong-Jin Wu
- Nicholas A. Meanwell*Nicholas A. Meanwell*Phone: (609) 252-6195. Email: [email protected]Department of Discovery and Chemistry and Molecular Technologies, Bristol-Myers Squibb PRI, PO Box 4000, Princeton, New Jersey 08543-4000, United StatesMore by Nicholas A. Meanwell
Abstract

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.
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