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Strategy for Extending Half-life in Drug Design and Its Significance

  • Hakan Gunaydin*
    Hakan Gunaydin
    Department of Modeling & Informatics, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115 United States
    *E-mail: [email protected]
  • Michael D. Altman
    Michael D. Altman
    Department of Modeling & Informatics, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115 United States
  • J. Michael Ellis
    J. Michael Ellis
    Department of Medicinal Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115 United States
  • Peter Fuller
    Peter Fuller
    Department of Medicinal Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115 United States
    More by Peter Fuller
  • Scott A. Johnson
    Scott A. Johnson
    Department of Modeling & Informatics, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115 United States
  • Brian Lahue
    Brian Lahue
    Department of Modeling & Informatics, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115 United States
    More by Brian Lahue
  • , and 
  • Blair Lapointe
    Blair Lapointe
    Department of Medicinal Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115 United States
Cite this: ACS Med. Chem. Lett. 2018, 9, 6, 528–533
Publication Date (Web):April 2, 2018
Copyright © 2018 American Chemical Society

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    Preclinical optimization of compounds toward viable drug candidates requires an integrated understanding of properties that impact predictions of the clinically efficacious dose. The importance of optimizing half-life, unbound clearance, and potency and how they impact dose predictions are discussed in this letter. Modest half-life improvements for short half-life compounds can dramatically lower the efficacious dose. The relationship between dose and half-life is nonlinear when unbound clearance is kept constant, whereas the relationship between dose and unbound clearance is linear when half-life is kept constant. Due to this difference, we show that dose is more sensitive to changes in half-life than changes in unbound clearance when half-lives are shorter than 2 h. Through matched molecular pair analyses, we also show that the strategic introduction of halogens is likely to increase half-life and lower projected human dose even though increased lipophilicity does not guarantee extended half-life.

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsmedchemlett.8b00018.

    • Changes in median in vivo CLu and in vivoVssu for the transformation exemplified, half-life change distributions for H → Me, H → Cl, H → CF3, Me → CF3, phenyl → pyridine, H → OH, and H → COOH transformations, and the plot of the relationship between in vivo clearance and bioavailability (PDF)

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