Thesis

The design, synthesis and optimisation of αvβ6 antagonists as potential idiopathic pulmonary fibrosis agents

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Creator
Awarding institution
  • University of Strathclyde
Date of award
  • 2013
Thesis identifier
  • T16456
Person Identifier (Local)
  • 201050889
Qualification Level
Qualification Name
Department, School or Faculty
Abstract
  • Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive disease of the interstitial lung. It is characterised by excessive deposition of fibrotic tissue with minimal associated inflammation. TGF-β1 is the primary cytokine implicated in fibrosis. The cytokine is found in an inactive complex that is activated by binding to the integrin via an RGD (Arg-Gly-Asp) sequence. In this report, the optimisation of a piperazine amide series of small molecule antagonists of the αvβ6 receptor is discussed with a view to their optimisation as potential IPF medicines. The report focuses on the optimisation of the piperazine amide in order to identify a compound suitable for delivery via inhalation of a nebulised solution to treat patients with IPF. The execution of a diverse set of synthetic routes allowed the syntheses of various novel compounds. Improvements in potency, selectivity and physicochemical properties were achieved to give the pyrrolidine compound with a 3,5-dimethylpyrazole group. The compound showed substantial increases in potency and selectivity and was selected as a pre-candidate by the Fibrosis DPU in February 2013. The 3,5-dimethylpyrazole with the R isomer of the pyrrolidine (347) was then screened for preliminary toxicology in a 14 day animal model where no adverse effects were observed. As a result, 347 was candidate selected in October 2013. Two kilograms of the molecule is currently being synthesised and is due to be dosed into man for the first clinical trial in early 2015. In addition, a rhodium catalysed asymmetric 1,4-addition reaction that has improved enantiomeric excess (ee) and reaction times over current literature conditions for similar scaffolds has been developed and published.
Advisor / supervisor
  • Suckling, Colin
  • Pritchard, John
Resource Type
Note
  • Previously held under moratorium in Chemistry department (GSK) from 20th May 2014 until 20th May 2019.
  • The confidentiality statement on each page of this thesis DOES NOT apply
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