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

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2018 Jun 26

PMID 29937977

Citations 20

Authors

Hakan Gunaydin

Michael D Altman

J Michael Ellis

Peter Fuller

Scott A Johnson

Brian Lahue

Blair Lapointe

Affiliations

Soon will be listed here.

Abstract

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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