Thesis
The design, synthesis and optimisation of calcium release-activated calcium (CRAC) channel inhibitors and mitochondrial permeability transition pore (mPTP) modulators, using phenotypic screening
- Creator
- Rights statement
- 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 drugmolecules reaching the market can be attributed to safety-related drug attrition.Additionally, the link between the physicochemical properties of small moleculedrugs and their toxicity profile has been demonstrated. Moreover, the type ofpharmacological assay used to measure the biological activity of compounds whencarrying out a drug discovery effort is critical to ensure the efficacy of compoundstowards modulating specific signalling pathways. Recent studies have suggested thatphenotypic screening, for which a target-agnostic measure of a biological response isused to develop an assay, can be more appropriate than target-based screening whendeveloping first-in-class small molecules in the context of under-defined biologicaltargets. This thesis describes the efforts in improving the physicochemical propertiesof small molecules, using phenotypic screening, towards the identification oftherapeutic agents modulating two biological targets, respectively: the calciumrelease-activated calcium channel and the mitochondrial permeability transition pore.CRAC channelThe allergen stimulation of immune cells such as T cells and mast cells triggers thedepletion of the calcium stores located in the endoplasmic reticulum, which in turnleads to an influx of calcium ions across the plasma membrane through calciumrelease-activated calcium (CRAC) channels. This process of store-operated calciumentry through CRAC channels is the main pathway of increasing the intracellularcalcium concentration in T cells and mast cells, which controls a wide range ofdownstream cellular functions, such as the release of pro-inflammatory cytokines andmediators like histamine and prostaglandins. Inhibiting the ion current passingthrough the CRAC channel (ICRAC) could help to modulate immune inflammatoryresponses, and thus development of an ICRAC blocker would be of considerableclinical interest to treat conditions such as asthma. The aim of the first medicinalchemistry programme described in this thesis is to identify selective small molecule oral ICRAC inhibitors as novel agents for the treatment of asthma and otherinflammatory diseases. This report describes the design, chemical synthesis andapplication of modern medicinal chemistry principles for the identification of novelICRAC blockers, starting from hit molecules originating from a high throughputscreen.mPTPThe mitochondrial permeability transition pore (mPTP) is a voltage sensitive proteinchannel present in the inner membrane of mitochondria and it plays a key role incellular apoptosis and necrosis. The exact composition of the pore is not fullyelucidated, however, it is thought to be a combination of several molecularconstituents. Under conditions of cellular stress, the channel transitions to a state ofhigh conductance and becomes non-selectively permeable to a wide range of soluteswhich freely diffuse into the mitochondria. Additionally, proteins contained in themitochondria, such as pro-apoptotic messengers, are released into the cytosol, whichleads to cell death. The sustained opening of the mPTP is believed to be a keytriggering event in the pathology of several diseases. The second part of this thesisdescribes the design and synthesis of small molecule modulators of the mPTP asnovel agents for the treatment of diseases mediated by the opening of the mPTP.
- Advisor / supervisor
- Ahmed, Mahmood
- Jamieson, Craig
- Hatley, Richard
- Resource Type
- Note
- Previously held under moratorium in Chemistry department (GSK) from 8 September 2015 until 18 June 2021.
- The confidentiality statement on each page of this thesis DOES NOT apply
- DOI
- Funder
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