Thesis

The development of small molecules for treatment of idiopathic pulmonary fibrosis (IPF)

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Awarding institution
  • University of Strathclyde
Date of award
  • 2015
Thesis identifier
  • T15954
Person Identifier (Local)
  • 20105429
Qualification Level
Qualification Name
Department, School or Faculty
Abstract
  • Idiopathic Pulmonary Fibrosis (IPF) is a chronic lung disease characterised by deposition of fibrotic tissue in the lungs. The exact cause of the disease is unknown; however it is possible that the condition may be triggered by either a chemical or biological insult. The death rate of IPF is high, with median survival rates from diagnosis of around three years. Current estimates suggest it is the 7th biggest killer in the UK, killing around 5000 people every year. An integrin (αvβ6) is known to interact with the TGFβ protein, which is known to be involved in cell growth, adhesion, migration and apoptosis as well as extracellular matrix (ECM) synthesis, and therefore αvβ6 could potentially be a therapeutic target for IPF. The first chapter in the thesis discusses the progression of small molecules for inhaled delivery. Compounds containing heterocyclic cores and with more sp3 character showed a favourable selectivity profile. This led to the development of compounds (R)-70a and (R)-80a, which showed superior levels of selectivity whilst maintaining potency. Compound (R)-70a was tested in PK studies and showed suitable properties for inhaled drug delivery. Compound (R)-80a is one of the most selective small molecules at αvβ6 integrin reported in the literature or measured in-house. Unfortunately compound (R)-80a was terminated due to a change in priority, however, there is now some evidence that a selective αvβ6 integrin compound might be useful on the inhaled programme and it is currently being used as a tool compound. The next chapter explored molecules suitable for oral drug delivery. These compounds showed either permeability or low protein binding, however both attributes are required for oral administration. Chapter four describes the development of a model to predict good oral properties based on the in-house data and the model is used in chapter five to develop a number of series. The fluoropyrrolidine series was identified, and exemplified by compound 211a, which was a potent inhibitor of the integrin receptor αvβ6 with high permeability and had a low protein binding. The compound also showed excellent oral bioavailability in both rat and dog PK studies. The concern about a metabolite being produced stimulated work to find an alternative replacement. The suggestion that a 2-(methoxy)ethoxy could replace the morpholine in compound 211a and this resulted in compound 239a. This compound showed superior PK properties when compared with compound 211a. Both compounds are currently being considered as small molecule anti-fibrotic medicines to be delivered to patients with fibrotic diseases with a dose around 30 – 550 mg per day. On-going experiments include a CT SPECT study, which will show if the compound binds to the αvβ6 integrin on the damaged epithelium or not. If it does bind, it may inhibit the activation of TGFβ and the production of collagen by active myofibroblasts. In doing so, it is expected to slow or stop the progression of fibrosis, providing significant benefits to patients allowing them to do more, feel better and live longer.
Advisor / supervisor
  • Patel, V.
  • Procopiou, Panayiotis A.
  • Percy, Jonathan
Resource Type
Note
  • Previously held under moratorium in Chemistry department (GSK) from 01/06/2015 until 18/06/2021.
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