Thesis

The design, synthesis and optimisation of calcium release-activated calcium (CRAC) channel inhibitors and mitochondrial permeability transition pore (mPTP) modulators, using phenotypic screening

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Awarding institution
  • University of Strathclyde
Date of award
  • 2015
Thesis identifier
  • T16062
Person Identifier (Local)
  • 201088051
Qualification Level
Qualification Name
Department, School or Faculty
Abstract
  • Several previous studies have shown that the current low success of new drug molecules reaching the market can be attributed to safety-related drug attrition. Additionally, the link between the physicochemical properties of small molecule drugs and their toxicity profile has been demonstrated. Moreover, the type of pharmacological assay used to measure the biological activity of compounds when carrying out a drug discovery effort is critical to ensure the efficacy of compounds towards modulating specific signalling pathways. Recent studies have suggested that phenotypic screening, for which a target-agnostic measure of a biological response is used to develop an assay, can be more appropriate than target-based screening when developing first-in-class small molecules in the context of under-defined biological targets. This thesis describes the efforts in improving the physicochemical properties of small molecules, using phenotypic screening, towards the identification of therapeutic agents modulating two biological targets, respectively: the calcium release-activated calcium channel and the mitochondrial permeability transition pore. CRAC channel The allergen stimulation of immune cells such as T cells and mast cells triggers the depletion of the calcium stores located in the endoplasmic reticulum, which in turn leads to an influx of calcium ions across the plasma membrane through calcium release-activated calcium (CRAC) channels. This process of store-operated calcium entry through CRAC channels is the main pathway of increasing the intracellular calcium concentration in T cells and mast cells, which controls a wide range of downstream cellular functions, such as the release of pro-inflammatory cytokines and mediators like histamine and prostaglandins. Inhibiting the ion current passing through the CRAC channel (ICRAC) could help to modulate immune inflammatory responses, and thus development of an ICRAC blocker would be of considerable clinical interest to treat conditions such as asthma. The aim of the first medicinal chemistry programme described in this thesis is to identify selective small molecule oral ICRAC inhibitors as novel agents for the treatment of asthma and other inflammatory diseases. This report describes the design, chemical synthesis and application of modern medicinal chemistry principles for the identification of novel ICRAC blockers, starting from hit molecules originating from a high throughput screen. mPTP The mitochondrial permeability transition pore (mPTP) is a voltage sensitive protein channel present in the inner membrane of mitochondria and it plays a key role in cellular apoptosis and necrosis. The exact composition of the pore is not fully elucidated, however, it is thought to be a combination of several molecular constituents. Under conditions of cellular stress, the channel transitions to a state of high conductance and becomes non-selectively permeable to a wide range of solutes which freely diffuse into the mitochondria. Additionally, proteins contained in the mitochondria, such as pro-apoptotic messengers, are released into the cytosol, which leads to cell death. The sustained opening of the mPTP is believed to be a key triggering event in the pathology of several diseases. The second part of this thesis describes the design and synthesis of small molecule modulators of the mPTP as novel agents for the treatment of diseases mediated by the opening of the mPTP.
Advisor / supervisor
  • Hatley, Richard
  • Ahmed, Mahmood
  • Jamieson, Craig
Resource Type
Note
  • Previously held under moratorium in Chemistry department (GSK) from 8 September 2015 until 18 June 2021.
DOI
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