Tau Protein Aggregation Inhibitors for the Treatment of Alzheimer's Disease

Abstract

Tau Protein Aggregation Inhibitors for the Treatment of Alzheimer’s Disease Alzheimer’s disease (AD) is an irreversible, neurodegenerative disorder. It is clinically characterised by episodic memory loss, behavioural disturbances, and progressive loss of cognitive function. With no definitive diagnostic, curative or preventative procedures in place for AD, development of disease modifying therapeutics is crucial. AD brains are characterised by two pathological hallmarks: the amyloid-β (Aβ) plaques and the neurofibrillary tangles (NFTs). NFTs are composed of the microtubule-associated protein tau. The dysregulation of tau function due to aggregation has been associated to the clinical symptomology of the disease. Inhibition of tau aggregation represents a promising avenue for the treatment of AD. Several potential tau aggregation inhibitors have been described in literature. However, chemical and biological properties have rendered these unsuitable as CNS-directed therapeutic agents. Recently, a novel compound, pyridinyl-butadienyl-benzothiazole-3 (PBB3), was reported as a high affinity ligand for tau aggregates and was subsequently developed as a PET imaging agent. Its ability to inhibit tau aggregation is currently unknown. This study aimed to assess the inhibitory activity of a library of compounds based on the PBB scaffold. Structural activity relationship (SAR) studies, involving variations in the core structure, will elucidate the key structural features that govern affinity to tau aggregates and lead to the development of drug candidates that inhibit tau aggregation. This thesis describes the synthesis of PBB3 and a number of analogues bearing modifications to the core structure. A superior synthetic pathway to access compounds of the PBB scaffold was developed and successfully employed to the synthesis of PBB3. A total of four analogues were tested in a ThT fluorescence assay to investigate their therapeutic potential as tau aggregation inhibitors.