| Summary: | Phosphoinositide-3-kinases (PI3Ks) are a family of lipid kinases which control a wide range of intracellular pathways implicated in inflammatory respiratory diseases. In this thesis, the optimisation of two chemical templates, (i) a pyridone series, and (ii) an aminopyrimidine series, is described, with the aim of finding a PI3Kγ selective smallmolecule inhibitor. Whilst work on the pyridone template did not result in any one compound which met allof the target criteria, progress was made in identifying analogues with significantly improved physicochemical properties. Furthermore, the exploration of this template has led to increased understanding of the PI3Kγ active site, which has enabled the design of isoform selective inhibitors such as a key imidate structure. Work on the aminopyrimidine series focused on improving the physicochemical profile for i.v. dosing. A prototype pro-drug was prepared, and profiled in blood stability and DMPK assays. Although its profile was not optimal, these results enabled the design of a second iteration of pro-drugs, with the aim of progressing to in vivo target validation studies. Further work on this series delivered significant improvements in the physicochemical properties of the template. Whilst this did not translate into improved cellular activity for this template, the learnings can now be applied to future work on novel cores. Finally, a programme of fragment-based drug discovery was initiated to identify novel templates as PI3Kγ inhibitors. Whilst an initial screen and follow-up chemistry delivered novel inhibitors with interesting profiles, concern over the physicochemical profile of the templates rapidly led to termination of this work. However, the subsequent design and screening of a bespoke fragment set, specifically targeting the identification of saturated or semi-saturated hinge binding fragments, was extremely successful. A variety of hits were indentified which provide exciting opportunities for the discovery of PI3Kγ inhibitors with the desired balance of biological and physicochemical profiles.
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