Thesis

The design and synthesis of small molecule inhibitors of mTOR Kinase for the treatment of idiopathic pulmonary fibrosis

Creator
Rights statement
Awarding institution
  • University of Strathclyde
Date of award
  • 2020
Thesis identifier
  • T16453
Person Identifier (Local)
  • 201691931
Qualification Level
Qualification Name
Department, School or Faculty
Abstract
  • Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease of the lung, characterised by excessive collagen deposition. A median survival time of 2-3 years gives IPF a worse prognosis than many cancers. The two currently approved treatments only slow progression of the disease, while the best treatment – a lung transplant – has long waiting lists, risks associated with organ rejection and is not a viable option for all patients. Researchers at GlaxoSmithKline (GSK) have demonstrated that inhibition of mTOR kinase halts the deposition of collagen. Research is underway to develop an inhaled small molecule inhibitor of mTOR kinase for the treatment of IPF. Chapter I describes the lead optimisation of a novel series of directly-linked sulfone mTOR kinase inhibitors (A, Figure). Compounds were designed and synthesised to explore structure activity relationships (SAR) by modifying the substituents at the 2-,4-, and 6-positions (R1, R2 and R3). The aims of this research were to: a) identify optimal combinations of the three substituents; b) synthesise compounds that met the target property profile (suitable efficacy, affinity and selectivity with no mutagenic risks); and c) investigate a range of novel sulfone moieties. While these aims were achieved, an in vivo study demonstrated that compounds from within this directlylinked sulfone series did not have the required in vivo efficacy. Figure: The two series of mTOR kinase inhibitors discussed in this Thesis. A – the directly-linked sulfone series and B – the carbon-linked sulfone series. Substituents in each of the three vectors coloured in red, green and blue. [Graphic element here] In parallel to the research into the directly-linked sulfone compound, an alternative series of carbon-linked sulfone mTOR kinase inhibitors was explored (B, Figure). As compounds in this series were progressed, larger quantities were needed, requiring a robust synthesis. Chapter II describes the work carried out to overcome the three key challenges in the synthesis: 1) To develop an improved synthesis of the 1-(5-chloro-1H-pyrrolo[3,2-b]pyridin-2-yl)-N-methylmethanamine moiety (E, Scheme, here referred to as the azaindole). 2) To improve the SNAr reaction conditions to install the (S)-3-ethylmorpholine to give compound C (Scheme). 3) To identify a suitable cross-coupling methodology to couple the 2-chloropyridine core (C) and the azaindole (E) to give final compound F. An improved synthesis of the azaindole (E) was designed, employing the Larock indole synthesis and a solvent and base screen gave improved conditions for the SNAr reaction to give compound C. Originally only feasible using Stille chemistry and toxic organostannanes, the bipyridyl cross-coupling reaction was improved by employing a desulfinative cross-coupling reaction (coupling D and E to give F, Scheme). Scheme: Forming the sulfinate and the successful desulfinative cross-coupling reaction. Reagents and Conditions: i) SMOPS (sodium 3-methoxy-3-oxopropane-1-sulfinate), Cu(I)I, DMSO, 110 °C. ii) NaOMe (0.5 M in MeOH), THF, 21 °C. iii) K2CO3, Pd(OAc)2, PCy3, 1,4-dioxane, 150 °C. iv) HCl (4 M in 1,4-dioxane), 1,4-dioxane. [Graphic element here] The scope of this desulfinative cross-coupling reaction was subsequently explored in Chapter III, with a particular focus on the synthesis of bipyridyl compounds. This demonstrated that a range of bipyridyl compounds could be made by this method. Finally, a high-throughput screening platform for the desulfinative cross-coupling reaction was designed and validated giving a rapid method to screen catalysts, bases and solvents and optimise the reaction. This proved particularly valuable to develop conditions for some of the more challenging cross-coupling substrates.
Advisor / supervisor
  • Burley, Glenn
  • Hobbs, Heather
Resource Type
Note
  • Previously held under moratorium in Chemistry Department (GSK) from 17/06/2020 to 14/12/2022
  • The confidentiality statement on each page of this thesis DOES NOT apply
DOI
Funder
Embargo Note
  • This thesis is restricted to Strathclyde users only until 17/06/2025

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