Design, Synthesis, and Evaluation of Lung-Retentive Prodrugs for Extending the Lung Tissue Retention of Inhaled Drugs.
Ayre J, Redmond JM, Vitulli G, Tomlinson L, Weaver R, Comeo E, Bosquillon C, Stocks MJ.
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 (<b>1</b>) through a pH-sensitive-linking group have been evaluated. Extensive optimization resulted in 1-(((<i>R</i>)-2-((<i>S</i>)-2,6-diaminohexanamido)-3,3-dimethylbutanoyl)oxy)ethyl 4-(2-hydroxy-2,2-diphenylacetoxy)piperidine-1-carboxylate (<b>23</b>), which combined very good <i>in vitro</i> stability and very high rat lung binding. Compound <b>23</b> progressed to pharmacokinetic studies in rats, where, at 24 h post dosing in the rat lung, the total lung concentration of <b>23</b> was 31.2 μM. In addition, high levels of liberated drug <b>1</b> 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.