Ayre, Jack
(2022)
Synthesis and Evaluation of Lung Tissue Retentive Prodrugs.
PhD thesis, University of Nottingham.
Abstract
In the time of a global respiratory pandemic, there has never been a more pertinent time to improve the current medications responsible for relieving the symptoms of respiratory diseases such as COPD and Asthma. Administration of drugs directly to the site of action through the pulmonary drug delivery route can give significant benefits over other traditional routes of administration i.e. oral. Avoidance of first pass metabolism in the liver, reduced drug dosage and significant reduction of compound exposure to other organs, ultimately leading to fewer side effects, are all benefits of the pulmonary delivery route. However, rapid drug elimination from lung tissue into the pulmonary vein, combined with the pan antagonistic nature of receptor antagonists and heavy presence of muscarinic receptors in other tissues, often leads to increased side effects in other organs, such as the heart.
Aims: The aim of this thesis was to design and evaluate a novel, self-activating, dibasic prodrug system as a possible method of achieving sustained delivery post inhalation. Evaluation of the method of increased lung tissue retention would then be explored using confocal microscopy to probe the lysosomal trapping potential of dibasic compounds. This system, if successful would represent a remarkable achievement in that the prodrug design could be developed to suit a wide range of chemical structures, and thus has the potential improve the inhaled PK profile of a wide variety of inhaled pharmaceuticals and thus massively expedite the development of novel-long acting treatments.
Chapter 1: Outlines the advantages of inhaled administration as a route for targeted drug delivery. In addition, it details the common mechanisms for achieving sustained drug delivery to the lung, alongside describing the pertinent need for new long acting muscarinic receptor antagonists in order to improve the current prevention and treatment of breathing difficulties in COPD and asthmatic patients.
Chapter 2: Describes the use of prodrug systems as mechanisms for improving drug delivery. In addition, it follows the development and implementation of a novel cleavable prodrug system from initial design stages, through to final in-vivo PK studies, as a method of efficaciously delivering an active muscarinic agent over a sustained period in attempt to increase the duration of action of an existing muscarinic receptor drug. It outlines the discovery of compound 24 as a novel, dibasic, pH-sensitive, self-cleaving, muscarinic prodrug capable of withstanding enzymatic cleavage in order to liberate an active muscarinic receptor antagonist at a sustained rate over 24 hours. The subsequent in-vivo pharmacokinetic studies demonstrate that when inhaled independently, over 99% of the active drug was eliminated from the lung tissue within 3 hours, but when delivered as a prodrug, sustained prodrug activation meant that the drug was present in the lung at a pharmaceutically relevant concentration for over 24 hours, with no detected exposure of the drug to blood plasma.
Chapter 3: Develops further the prodrug system introduced in chapter 1, this time focusing on an intracellular PI3K δ target. It follows an attempt to improve an intermediate drug candidate which suffered from poor physiochemical properties and thus did not progress to clinical trials. Included is the design and attempted synthesis of a series of prodrugs, which based on the results of chapter 1, would be interesting candidates for an in-vivo PK study to determine their duration of action relative to the parent drug candidates, and thus feasibility as sustained release delivery agents.
Chapter 4: Investigates how the dibasic moiety of the prodrug design affects the distribution of the prodrug in lung tissue. By taking a lysosome-targeting fluorescent probe, replacing the functionality responsible for its lysosome targeting nature with the dibasic prodrug moiety, a distribution comparison can be created. This chapter attempted to visualise the effect of incorporating a dibasic moiety into the prodrug design on the distribution and organelle sequestration.
Conclusion: A dibasic, self-activating prodrug (Compound 24) has been created which displays a much-increased lung tissue retention relative to the parent drug (Compound 1). Post intratracheal dosing, sustained release of 1 from 24 resulted in a high, pharmaceutically relevant concentration of 1 in the lung tissue for over 24 hours all from a single dose. Thus, the unique approach of using a prodrug system which incorporates lung tissue retentive chemical moieties to extend the lung residency time of a muscarinic antagonist has been successful. Further studies will determine whether an extended pharmacodynamic response has also been achieved and will help to elucidate the mechanism of lung retention.
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