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

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.