Small molecule Bromodomain and Extra-Terminal (BET) inhibitors have shown promising therapeutic interest in oncology and immuno-inflammation. However, clinical studies have shown limited therapeutic window for pan-BET inhibitors, restricting their use to aggressive oncology indications. A macrophage-targeted approach, using the Esterase Sensitive Motif (ESM) technology, is being investigated in our laboratories. The first ESM-BET inhibitor is currently progressing through clinical studies for the treatment of rheumatoid arthritis. This cell-targeted approach has so far demonstrated reduced toxicity in preclinical animal studies. Due to the attrition rate during drug development, a second ESM-BET inhibitor is desired. In this thesis, a novel series of ESM-BET inhibitors is investigated. The initial molecules demonstrated high in vitro clearance in human and monkey species. This was rationalised as due to a lack of carboxyl esterase (CES) selectivity, in particular between CES-1 (desired) and CES-2 (undesired). The current study describes how CES-1 vs. CES-2 selectivity was achieved. Further optimisation efforts led to the discovery of two advanced molecules with suitable profiles for progression into in vivo PK studies. In parallel to the medicinal chemistry optimisation, the synthetic route towards the key benzazepinone motif was improved in terms of yields, step count and robustness, enabling scale up to support investigation of multiple BET inhibitor series
within our laboratories. Finally, partial racemisation of two chiral centres was identified during lead optimisation. A stereoselective route was established to address this issue, providing crystalline material in excellent e.e. and good yields throughout the synthetic route to support the progression of the molecules in in vivo studies.
| Date of Award | 11 Mar 2020 |
|---|
| Original language | English |
|---|
| Awarding Institution | - University Of Strathclyde
|
|---|
| Sponsors | University of Strathclyde |
|---|
| Supervisor | Craig Jamieson (Supervisor) & William Kerr (Supervisor) |
|---|