Signal transduction pathways involving kinases are implicated ininflammatory airway diseases. The modulation of two kinases, IKK2 and PI3Kδ, was explored for the treatment of airway diseases such as asthma and Chronic Obstructive Pulmonary Disease. Small molecule inhibitors of IKK2 and PI3Kδ were designed using a variety of drug design strategies. A Hansch analysis was carried out to investigate the quantitative structure activity relationships of a series of 3,5-substituted indole carboxamide compounds. This led to the design and synthesis of a set of novel IKK2 inhibitors. Ligand efficiency was used to focus on compounds with the optimal combination of physicochemical and pharmacological properties and 3-cyano-substituted indole carboxamides were discovered as ligand efficient inhibitors of IKK2. Homology modelling and knowledge from the contemporary medicinal chemistry literature aided the design of an alternative 3-position substituent and this led to the challenging syntheses of IKK2 inhibitors incorporating the 3-oxetanyl group. The chemistries explored led to the discovery of a novel oxazole formation from primary amides and 3-oxetanone, which represented a highly competitive method for formation of these heteroarenes. Structure-based drug design was utilised to design a series of PI3Kδ inhibitors. 4-Substituted dihydroisobenzofurans were synthesised and conformational analyses showed that potent PI3Kδ inhibitors bound to the enzyme in low energy conformations. Crystal structures of the inhibitor-enzyme complexes identified additional interactions required for PI3Kδ potency and selectivity over related PI3Ks. Amides or ethers based on the 4-(dihydroisobenzofuranyl) core were preferred; however the oral PK profile of the compounds required optimisation. Strategies to reduce metabolic clearance were implemented, including reducing lipophilicity and incorporating metabolically stable groups. A set of compounds were synthesised and analysis of the data showed that lipophilicity was not a good predictor of metabolic clearance. However, the in vitro microsomal stability assay effectively predicted in vivo clearance and will now be used routinely as a screen for future compounds.From this optimisation work, a PI3Kδ inhibitor with a superior oral drug profile and significantly reduced predicted once-daily human dose was discovered.
|Date of Award||1 Jun 2014|
- University Of Strathclyde