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Design, Synthesis, and Evaluation of Lung-Retentive Prodrugs for Extending the Lung Tissue Retention of Inhaled Drugs

Ayre, Jack; Redmond, Joanna M; Vitulli, Giovanni; Tomlinson, Laura; Weaver, Richard; Comeo, Eleonora; Bosquillon, Cynthia; Stocks, Michael J.

Design, Synthesis, and Evaluation of Lung-Retentive Prodrugs for Extending the Lung Tissue Retention of Inhaled Drugs Thumbnail


Authors

Jack Ayre

Joanna M Redmond

Giovanni Vitulli

Laura Tomlinson

Richard Weaver

Eleonora Comeo

MICHAEL STOCKS MICHAEL.STOCKS@NOTTINGHAM.AC.UK
Professor of Medicinal Chemistry and Drug Discovery



Abstract

A major limitation of pulmonary delivery is that drugs can exhibit suboptimal pharmacokinetic profiles resulting from rapid elimination from the pulmonary tissue. This can lead to systemic side effects and a short duration of action. A series of dibasic dipeptides attached to the poorly lung-retentive muscarinic M3 receptor antagonist piperidin-4-yl 2-hydroxy-2,2-diphenylacetate (1) through a pH-sensitive-linking group have been evaluated. Extensive optimization resulted in 1-(((R)-2-((S)-2,6-diaminohexanamido)-3,3-dimethylbutanoyl)oxy)ethyl 4-(2-hydroxy-2,2-diphenylacetoxy)piperidine-1-carboxylate (23), which combined very good in vitro stability and very high rat lung binding. Compound 23 progressed to pharmacokinetic studies in rats, where, at 24 h post dosing in the rat lung, the total lung concentration of 23 was 31.2 μM. In addition, high levels of liberated drug 1 were still detected locally, demonstrating the benefit of this novel prodrug approach for increasing the apparent pharmacokinetic half-life of drugs in the lungs following pulmonary dosing.

Citation

Ayre, J., Redmond, J. M., Vitulli, G., Tomlinson, L., Weaver, R., Comeo, E., …Stocks, M. J. (2022). Design, Synthesis, and Evaluation of Lung-Retentive Prodrugs for Extending the Lung Tissue Retention of Inhaled Drugs. Journal of Medicinal Chemistry, 65(14), 9802-9818. https://doi.org/10.1021/acs.jmedchem.2c00416

Journal Article Type Article
Acceptance Date Jun 24, 2022
Online Publication Date Jul 7, 2022
Publication Date Jul 28, 2022
Deposit Date Jul 1, 2022
Publicly Available Date Mar 29, 2024
Journal Journal of medicinal chemistry
Print ISSN 0022-2623
Electronic ISSN 1520-4804
Publisher American Chemical Society (ACS)
Peer Reviewed Peer Reviewed
Volume 65
Issue 14
Pages 9802-9818
DOI https://doi.org/10.1021/acs.jmedchem.2c00416
Keywords Drug Discovery; Molecular Medicine
Public URL https://nottingham-repository.worktribe.com/output/8769944
Publisher URL https://pubs.acs.org/doi/10.1021/acs.jmedchem.2c00416

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