Approaches to lead generation for idiopathic pulmonary fibrosis targets

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.

Name dc:type.qualificationname

phd

Level dc:type.qualificationlevel

doctoral-pg

Grantor dc:publisher.institution

University of Strathclyde

Year dc:date.issued

2016

Author dc:creator

• Duffy, Emma

Advisors dc:contributor.advisor

• Watson, Allan
• Macdonald, Simon
• Jamieson, Craig
• Pritchard, John

DOI

10.48730/dsp1-at05

Identifier

T14467

Author Identifier

201266727

OAI identifier oai:identifier

oai:strathclyde:7m01bk74n