Metabolic Stability of Fluorinated Small Molecules: A Physical Organic Chemistry Perspective.

Authors

Pankaj Bhattarai, Trevor A Trombley, Ryan A Altman

Published in

Journal of medicinal chemistry. Jan 21, 2026. Epub Jan 21, 2026.

Abstract

The incorporation of fluorine and fluorinated motifs into medicinally relevant scaffolds can improve the metabolic and pharmacokinetic properties (DMPK) of drug molecules. Typically, this phenomenon is attributed to differences in C-H vs C-F bond strengths, though such an explanation ignores accepted mechanisms of drug metabolism and how fluorine and fluorinated substituents perturb the physicochemical properties of small molecules. Instead of relying on bond strengths, this perspective will review established mechanisms of drug metabolism and provide a mechanistic rationale for the improved metabolic profiles achieved by fluorinating drug candidates. This discussion will connect observed trends in structure-metabolism relationships with known mechanistic features of relevant drug-metabolizing enzymes, with the ultimate goal of improving medicinal chemistry decision-making.

PMID:
41564243
Bibliographic data and abstract were imported from PubMed on 22 Jan 2026.

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