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

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.

Prodrugs as empowering tools in drug discovery and development: recent strategic applications of drug delivery solutions to mitigate challenges associated with lead compounds and drug candidates

“…While pulmonary drug delivery via inhalation has been successful in the treatment of a number of respiratory disorders, including asthma and chronic obstructive pulmonary disease Table 30 Dimeric prodrug approach for the antipsychotic drug 5ae designed to inhibit P-gp and ABCG2, which limit BBB exposure (COPD), a major drawback can be the rapid elimination of drugs from pulmonary tissue resulting in short duration of action in the lungs and high exposure in the blood that can be associated with systemic side effects. 90 As part of an effort to improve the therapeutic index and reduce the frequency of administration of inhaled therapies, a prodrug approach was considered as a means of enhancing the lung residence time of the muscarinic M 3 receptor antagonist 6bv, an active metabolite of enpiperate (6bu), as the model of a drug with poor lungretention (Table 31). Accordingly, prodrugs were designed that incorporated a dibasic promoiety to facilitate lung retention with a pH-triggered release linker.…”

“…Hence, dose-limited efficacy and dose-related toxicities due to off-target effects have been major bottlenecks in advancing potent drug candidates. Prodrugs have been explored to improve drug delivery to specific human organs or tissues, including the colon, 80,81 the lymphatic system, 82,83 the liver, 84,85 the kidney, 86 the central nervous system (CNS), [87][88][89] and the lung, 90 with the design aspects typically focusing on tissue-selective activation or the exploitation of targetspecific carriers at the site of interest. Prodrug design approaches have also been found to be useful in topical drug delivery, including ocular administration, [91][92][93] and to specifically target microbes like viruses, 94,95 bacteria, 96 and parasites.…”