Optimization and development of novel small molecule inhibitors of beta-amyloid aggregation for the treatment of Alzheimer's disease. (360G-Wellcome-084089_Z_07_D)

Current treatments for Alzheimer's disease (AD) only produce temporary symptomatic relief and there is a definite unmet medical need for disease-modifying therapies that can significantly delay its progression. Abnormally folded protein species associated with AD have been characterised with regard to their detrimental effects on cognitive function and there is emerging consensus that soluble oligomeric forms of beta-amyloid (Abeta) represent the primary pathological species. Senexis has identified a series of small molecule drug-like compounds which are believed to block the generation of soluble forms of Abeta and their toxic effects. They have clear therapeutic potential and the next phase of optimisation now needs to be undertaken to generate molecules that will be suitable candidates for clinical development for the treatment of AD. The first part of the project will complete the optimisation of key properties of these molecules, including their potency, oral bioavailability and CNS penetration. This will use structure activity relationships generated in the initial programme of the work conducted by Senexis. With this achieved, preliminary safety screening of candidate molecules will be undertaken from which the best one will be selected for pre-clinical development, the successful outcome of which will provide a molecule for clinical evaluation in man.