Thesis
αV integrin antagonists for the treatment of idiopathic pulmonary fibrosis
- Creator
- Awarding institution
- University of Strathclyde
- Date of award
- 2020
- Thesis identifier
- T16427
- Person Identifier (Local)
- 201650796
- Qualification Level
- Qualification Name
- Department, School or Faculty
- Abstract
- Herein are described two investigations of αv integrin antagonists for the treatment of Idiopathic Pulmonary Fibrosis (IPF). Previous studies have implicated several αV containing integrins as having an important role in the onset of fibrotic disease in several organs.In the first of the projects described, the unusual properties of 1 (Figure 1) have been investigated. Compound 1 is an αVβ6 antagonist, a candidate molecule for IPF. This molecule possesses greater permeability than its diastereomers, and it was hypothesised that this is the result of a conformational effect. In particular, the propensity for these, and related compounds, to form a transient intramolecular hydrogen bond (IMHB) when permeating, leading to shielding of the polarity of the molecule, has been investigated. Several close analogues of 1 have been synthesised, which imply a conformational effect is present, and nuclear magnetic resonance (NMR) investigations, in particular using 15N NMR, give evidence for IMHB formation. The 15N NMR spectroscopic data gives a quantitative indication of the differing extent of IMHB formation between compounds. Other similar αVβ6 antagonists have been investigated using this approach, helping to validate this method, as their 15N NMR shifts correlate with their permeability, relative to their lipophilicity. The results observed have been corroborated by computational calculations. The extent of IMHB formation of a group of previously synthesised αV integrin antagonists has been predicted using these calculations, and 15N NMR measurements have been compared to the predictions. The success of these predictions shows that, to an extent, it is possible to predict the extent of IMHB formation, which will help future medicinal chemistry efforts where designing passively permeable compounds is a challenge. In the second project, structure-activity relationship (SAR) studies on a series of tetrahydroazepine compounds as αVβ1 integrin antagonists were performed (Figure 2). The αVβ1 integrin appears to have a role in tissue fibrosis, although a relative paucity of investigations on this integrin have been carried out, largely due to the lack of selective tool compounds available. Beginning from a previous series of orally bioavailable αVβ3 and αVβ5 selective compounds, the aims of this work were to obtain potency at the αVβ1 integrin, whilst moving the series into previously unexemplified chemical space, and ideally to also obtain selectivity over the other integrins, particularly αVβ3 and αVβ5. This work has been computationally guided, using an αVβ1 homology model to first rationalise the potency of compounds, then latterly to design new analogues. A group of analogues with different aromatic cores and different linker atoms have been synthesised, each with a bespoke route. It has been found that it is possible to include heterocycles within the core of the molecule, but changing the ether linkage to the chain to a carbon atom is not tolerated. The potency of these compounds could be rationalised by evaluation of the docked conformations of these compounds in the homology model. Consequently, the docking model was used prospectively, in order to design compounds that were selective for αVβ1 over αVβ3, by comparing the receptor of the αVβ3 crystal structure with the αVβ1 homology model. Late-stage modifications were carried out to rapidly generate a range of substitution at two different positions. Unfortunately, however, selectivity for the αVβ1 has remained elusive, and this part of the work has highlighted the limitations of the use of homology model docking in ligand design. [Figures available in print copy]
- Advisor / supervisor
- Kerr, William J.
- Pritchard, John
- Resource Type
- Note
- Previously held under moratorium from 17th June 2020 until 22nd November 2022. GSK - held in Chemistry Department during moratorium.
- DOI
- Funder
- Embargo Note
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