This thesis explores the development of inhibitors for phosphoinositide 3-kinase δ(PI3Kδ), a lipid kinase implicated in COPD related inflammation. Firstly, a macrocyclisation approach was explored (Figure 1), this involved design,synthesis and profiling of macrocyclic analogues of the ‘benzoxazine’ series of PI3Kδinhibitors. This approach showed macrocycles could provide lead-like compounds,with a number of macrocycles exhibiting potency gains, up to 200-fold, over acyclic progenitor compounds. Next, the effect of macrocyclisation on other relevant properties for drug discovery was examined. It was established that a number of these macrocycles are water soluble, permeable, low clearance compounds. Differences with acyclic compounds were observed in subsets of compounds, however broad conclusions about the effect of macrocyclisation could not be drawn.In the second part of this study, synthetic methodology was developed for the synthesis of cyclopropyl boronic esters (Figure 2). Synthesis of compounds containing this functionality allows facile incorporation of three-dimensional character into drug-like scaffolds. A reaction manifold was developed utilising Schwartz’s Reagent for the conversion of synthetically tractable propargylic silyl ethers into complex products ina one-pot procedure, exemplified by the synthesis of aryl-, aliphatic-, quaternary- and spiro- substituted cyclopropyl boronic esters. The methodology was applied to enable a new synthesis of biologically active Sedaxane, via a bis-cyclopropyl boronic ester motif and to explore a growth vector from a cyclopropyl ring in an emerging series of PI3Kδ inhibitors.
| Date of Award | 18 May 2018 |
|---|
| Original language | English |
|---|
| Awarding Institution | - University Of Strathclyde
|
|---|
| Sponsors | University of Strathclyde & Glaxo Smithkline (UK) |
|---|
| Supervisor | Craig Jamieson (Supervisor) & John Murphy (Supervisor) |
|---|