Thesis

Approaches to lead generation for idiopathic pulmonary fibrosis targets

Downloadable Content

Download PDF
Creator
Rights statement
Awarding institution
  • University of Strathclyde
Date of award
  • 2016
Thesis identifier
  • T14467
Person Identifier (Local)
  • 201266727
Qualification Level
Qualification Name
Department, School or Faculty
Abstract
  • Idiopathic pulmonary fibrosis (IPF) is a common and devastating lung disease. There is currently no cure for IPF, and the limited pharmaceutical agents available to patients do not improve lung function, and only give moderate improvements in quality of life. Consequently, IPF is a major cause of morbidity and mortality around the world, and an area of large unmet medical need. The exact aetiology of IPF is poorly defined, however, there is evidence in the literature that this disease is mediated by the ATX-LPA pathway (Scheme 1 [see thesis for details]). AM095 and PF-8380 are compounds known to modulate the ATX-LPA pathway, by inhibition of the LPA receptor or the ATX enzyme, respectively. Using these literature templates, AM095 and PF-8380, as starting points, a hit-to-lead approach was implemented towards identifying new compounds as a treatment for IPF. Accordingly, a rational drug design approach was pursued with the aim of creating novel, simple molecules derived from these two progenitor compounds, whilst strategically retaining key pharmacophoric elements of AM095 and PF-8380 hypothesised to be crucial for activity. Following the design and synthesis of these novel entities, a range of biological assays were performed. The assays assessed the pharmacological potential of the compounds to disrupt the ATX-LPA signalling pathway. With regard to the hit-to-lead trajectory utilising AM095, a cross-screening approach was undertaken through simultaneously screening at both validated targets, LPA1 and ATX. Using a scaffold hopping approach, a more minimalistic chemotype was identified with improved physicochemical properties. In the PF-8380 derived series, a structure-based drug design approach was undertaken to fully understand binding interactions involved in ATX inhibition. Using biostructural and structure activity relationship data, the binding interactions required for ATX inhibition were defined for this chemotype. An iterative drug design cycle was employed which led to the identification of novel high quality ATX inhibitors. With suitable further biological evaluation the analogues identified in this work could be of utility as new treatment units for the intractable disease, IPF.
Advisor / supervisor
  • Watson, Allan
  • Macdonald, Simon
  • Jamieson, Craig
  • Pritchard, John
Resource Type
Note
  • Previously held under moratorium from 1st December 2016 until 1st December 2021
DOI
Date Created
  • 2016
Former identifier
  • 9912537592802996
Funder

Relations

Items

Thumbnail Title Date Uploaded Visibility Actions
file details PDF of thesis T14467 2021-07-02 Public Download