This thesis describes the design and synthesis of small molecule epigenetic inhibitors, motivated by the identification of disease treatments which will provide innovative medicines for patients. The work reported is focused on the identification of compounds which bind to the bromodomains of the BET family of proteins. These bromodomains have been implicated in a number of therapeutic areas, including oncology and immuno-inflammatory diseases. In Part I, an introduction to current challenges in drug discovery sets the scene for the work reported within this thesis. The science of epigenetics is introduced, and key medicinal chemistry themes relevant to these PhD studies are presented. In Part II, an orally bioavailable BET bromodomain inhibitor suitable for clinical progression was identified, the first such example from the dimethylisoxazole series of compounds. Medicinal chemistry was focused on SAR generation, and the control of physicochemical properties by the use of in silico profiling. Ultimately, the pre-clinical candidate molecule was synthesised on a large scale to provide material for further in vivo safety and efficacy studies. In Part III, esterase sensitive motif (ESM) technology was used to target molecules to cells of the monocyte/macrophage lineage with the aim of improving tolerability. ESM technology was incorporated into BET bromodomain inhibitors, and molecules were identified to probe the viability of this approach in the BET bromodomain area. In Chapter 3, preliminary work was undertaken to establish a successful proof of principle for the use of ESM technology within the BET bromodomain area. In Chapter 4, the chemical series was further developed, resulting in an increased cellular potency of the molecules. As a result, an in vitro probe molecule was identified which could be used to further elucidate BET- ESM technology. In Chapter 5, medicinal chemistry design was focused on improving the drug-like properties of the series, increasing cellular permeability, and reducing in vitro clearance. By balancing these properties, a molecule was identified for in vivo profiling, and is currently under investigation to assess its suitability as a pre-clinical candidate molecule.
|Date of Award||13 Oct 2014|
- University Of Strathclyde