School of Pharmacy, Biodiscovery Institute, University Park Nottingham, Nottingham NG7 2RD, U.K.
GSK Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, U.K.
J Med Chem. 2022 Jul 28;65(14):9802-9818. doi: 10.1021/acs.jmedchem.2c00416. Epub 2022 Jul 7.
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 () through a pH-sensitive-linking group have been evaluated. Extensive optimization resulted in 1-((()-2-(()-2,6-diaminohexanamido)-3,3-dimethylbutanoyl)oxy)ethyl 4-(2-hydroxy-2,2-diphenylacetoxy)piperidine-1-carboxylate (), which combined very good stability and very high rat lung binding. Compound progressed to pharmacokinetic studies in rats, where, at 24 h post dosing in the rat lung, the total lung concentration of was 31.2 μM. In addition, high levels of liberated drug 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.
肺部给药的一个主要限制是，由于药物从肺部组织中迅速消除，药物可能表现出不理想的药代动力学特征。这可能导致全身副作用和作用持续时间短。通过 pH 敏感连接基团将一系列连接到肺部保留能力差的毒蕈碱 M3 受体拮抗剂哌啶-4-基 2-羟基-2,2-二苯基乙酸酯（）的双碱性二肽进行了评估。广泛的优化导致 1-((()-2-((()-2,6-二氨基己酰胺基)-3,3-二甲基丁酰基)氧基)乙基 4-(2-羟基-2,2-二苯基乙酰氧基)哌啶-1-羧酸酯（），它结合了非常好的稳定性和非常高的大鼠肺结合。化合物在大鼠中进行了药代动力学研究，在大鼠肺部给药后 24 小时，肺部中总浓度为 31.2 μM。此外，仍局部检测到大量游离药物，这表明这种新型前药方法可用于增加肺部给药后药物在肺部的表观药代动力学半衰期，从而带来益处。
