학술논문
Design, Synthesis, and Evaluation of Lung-Retentive Prodrugs for Extending the Lung Tissue Retention of Inhaled Drugs.
Document Type
Academic Journal
Author
Ayre J; School of Pharmacy, Biodiscovery Institute, University Park Nottingham, Nottingham NG7 2RD, U.K.; Redmond JM; GSK Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, U.K.; Vitulli G; GSK Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, U.K.; Tomlinson L; GSK Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, U.K.; Weaver R; XenoGesis Ltd, Discovery Building, BioCity, Pennyfoot Street, Nottingham NG1 1GR, U.K.; Comeo E; School of Pharmacy, Biodiscovery Institute, University Park Nottingham, Nottingham NG7 2RD, U.K.; Bosquillon C; School of Pharmacy, Boots Science Building, University Park Nottingham, Nottingham NG7 2RD, U.K.; Stocks MJ; School of Pharmacy, Biodiscovery Institute, University Park Nottingham, Nottingham NG7 2RD, U.K.
Source
Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE
Subject
Language
English
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.