Synthesis enabled drug discovery

Rights statement
Awarding institution
  • University of Strathclyde
Date of award
  • 2017
Thesis identifier
  • T16435
Person Identifier (Local)
  • 201359523
Qualification Level
Qualification Name
Department, School or Faculty
  • This thesis describes the development and application of key organic synthesis methods to enable two different drug discovery projects: the development of inhibitors of lipoprotein-associated phospholipase A2 (Lp-PLA2), and the bromodomain and extra terminal (BET) family. Studies have implicated the phospholipase Lp-PLA2 in a range of different disease states, including cardiovascular disorders, diabetic macular oedema, and Alzheimer’s disease. With the aim of developing novel inhibitors of Lp-PLA2, a fragment screening approach was used to identify small, ligand efficient, cyclic borolane inhibitors. The potency and selectivity could be enhanced by careful structure guided growth. The novel cyclic borolane template posed a number synthetic challenges. The first section of the thesis describes the synthesis and evaluation of a novel subset of pyridone borolane inhibitors of Lp-PLA2. This research led to the identification of a novel iridium-mediated carbenoid insertion reaction that was applicable to all borolane analogues. Development and optimisation of this reaction led to methodology which was employed in our laboratories to rapidly assemble a range of synthetically challenging borolane analogues in high yields. This led to the identification of a key pyridyl borolane. The established iridium chemistry provided the ability to rapidly enable scale-up and biological evaluation of this compound. Further synthetic research led to the identification of a new concise asymmetric route to provide the desired key compound in excellent yields and enantioselectivities. The second section of the thesis describes the development of a novel, synthetically challenging series of BET inhibitors. Inhibition of the BET family of bromodomains has been implicated in a range of different disease states, including cancer. The work describes the development of a new series of constrained BET inhibitors, to remove a functional group of concern. This new series was found to retain the potency exhibited by the original series, without the potentially reactive functionality. If required, this series could form the basis of a new research project and be developed into a novel series of BET inhibitors by further elaboration. In addition to this, the synthetic work on the BET series led to the identification of a new rhodium-catalysed, directed C-H activation reaction. It was envisaged that this methodology could be applied to enable the more facile synthesis of a diverse range of medicinal chemistry targets.
Advisor / supervisor
  • Patel, Vipulkumar
  • White, Gemma
  • Kerr, William J.
Resource Type
  • The confidentiality statement on each page of this thesis DOES NOT apply.
  • Previously held under moratorium in Chemistry department (GSK) from 10 October 2017 until 22 November 2022.