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., Bosquillon, C., & 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