Chromatographic Determination of Permeability-Relevant Lipophilicity Facilitates Rapid Analysis of Macrocyclic Peptide Scaffolds.

Autor:	Koch G; Department of Chemistry and Biochemistry, University of California, Santa Cruz, 1156 High St., Santa Cruz, California 95064, United States., Engstrom A; Department of Chemistry and Biochemistry, University of California, Santa Cruz, 1156 High St., Santa Cruz, California 95064, United States., Taechalertpaisarn J; Department of Chemistry and Biochemistry, University of California, Santa Cruz, 1156 High St., Santa Cruz, California 95064, United States., Faris J; Department of Discovery Chemistry, Revolution Medicines, Inc., Redwood City, California 94063, United States., Ono S; Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Kanagawa 227-0033, Japan., Naylor MR; Department of Chemistry and Biochemistry, University of California, Santa Cruz, 1156 High St., Santa Cruz, California 95064, United States., Lokey RS; Department of Chemistry and Biochemistry, University of California, Santa Cruz, 1156 High St., Santa Cruz, California 95064, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2024 Nov 14; Vol. 67 (21), pp. 19612-19622. Date of Electronic Publication: 2024 Oct 25.
DOI:	10.1021/acs.jmedchem.4c01956
Abstrakt:	Hydrocarbon-determined shake-flask measurements have demonstrated great utility for optimizing lipophilicity during early drug discovery. Alternatively, chromatographic methods confer reduced experimental error and improved handling of complex mixtures. In this study, we developed a chromatographic approach for estimating hydrocarbon-water shake-flask partition coefficients for a variety of macrocyclic peptides and other bRo5 molecules including PROTACs. The model accurately predicts experimental shake-flask measurements with high reproducibility across a wide range of lipophilicities. The chromatographic retention times revealed subtle conformational effects and correlated with the ability to sequester hydrogen bond donors in low dielectric media. Estimations of shake-flask lipophilicity from our model also accurately predicted trends in MDCK passive cell permeability for a variety of thioether-cyclized decapeptides. This method provides a convenient, high-throughput approach for measuring lipophilic permeability efficiency and predicting passive cell permeability in bRo5 compounds that is suitable for multiplexing pure compounds or investigating the properties of complex library mixtures.
Databáze:	MEDLINE
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