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.

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: Jul 8, 2023
• Journal: Journal of medicinal chemistry
• Print ISSN: 0022-2623
• Electronic ISSN: 1520-4804
• Publisher: American Chemical Society
• 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