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

Autor: Hakan Gunaydin, Scott A. Johnson, Brian R. Lahue, Blair T. Lapointe, J. Michael Ellis, Michael D. Altman, Peter Fuller
Rok vydání: 2018
Předmět:
Zdroj: ACS Medicinal Chemistry Letters. 9:528-533
ISSN: 1948-5875
DOI: 10.1021/acsmedchemlett.8b00018
Popis: [Image: see text] 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.
Databáze: OpenAIRE
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