Thesis

The synthesis and optimisation of toll-like receptor agonists as potential immunomodulatory agents

Creator
Rights statement
Awarding institution
  • University of Strathclyde
Date of award
  • 2016
Thesis identifier
  • T15198
Person Identifier (Local)
  • 201051538
Qualification Level
Qualification Name
Department, School or Faculty
Abstract
  • Toll like receptors (TLRs) detect pathogenic compounds and trigger the innate immune defences. In addition, the activation of TLRs can have profound effects on the immune system. The activation of TLR7 in plasmacytoidal dendritic cells leads to the production of the cytokine interferon-α (IFNα). Through a variety of mechanisms, this cytokine polarises the adaptive immune system, enhancing the body's ability to kill the invading organism. Historically, small molecule agonists of TLR7 have been shown to exert an antiviral effect. However, the research presented in this thesis focuses on the potential of such a small molecule TLR7 agonist to treat allergic diseases. Allergic diseases are characterised by an inappropriate response by the immune system to otherwise benign substances called allergens (e.g. pollen, catdander etc). This response is driven by the so called TH2 component of the adaptive component of the immune system. It is proposed that such allergic responses can be reduced in both the short and long term by administration of a small molecule TLR7 agonist, through its ability to rebalance the immune system. This should lead to acessation of symptoms and potential long term therapeutic benefit. Two chemical series have been investigated: 2-aminopyrimidines and 9-deazaadenines. The initial 2-aminopyrimidine hit A was identified following a high throughput screen and converted to lead compounds B and C. [Formula 1 in the abstract cannot be replicated here - see thesis for details] Employing molecular modelling tools, the 6-position was identified as a potential point for further optimisation. Subsequent synthesis and biological profiling has enabled the molecular model to be evaluated. The second series of compounds is based on a 9-deazaadenine core. Hit compound D was modified to furnish lead compound E. The SAR at the two and seven positions has been investigated resulting in the optimised compound, a potential clinical candidate F. The biological and preclinical toxicological profile of compound F is described in detail. The deazaadenine series of compounds has also been optimised for potential use in the treatment of Actinic Keratosis. [Formula 2 in abstract cannot be replicated here - see thesis for details]
Advisor / supervisor
  • Coe, Diane
  • Jamieson, Craig
Resource Type
Note
  • Previously held under moratorium in Chemistry Department (GSK) from May 2016 until May 2018.
  • The confidentiality statement on each page of this thesis DOES NOT apply
DOI
Date Created
  • 2016
Former identifier
  • 9912708391702996
Funder

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