Pharmacophore Exploration of Small Molecules Targeting Protein Aggregation for the Treatment of Neurodegenerative Diseases

Abstract

The treatment of neurodegenerative disease states that cause dementia, such as Alzheimer’s Disease (AD) and Frontotemporal Dementia (FTD), is one of the most significant challenges facing modern medicine. Targeting pathological aggregates of proteins such as transactive response DNA-binding protein 43 kDa (TDP-43) and microtubule associated protein tau has been identified as a possible therapeutic avenue for the development of disease- modifying treatments for a range of neurodegenerative conditions. The exploration of pharmacophores in the optimisation of drug candidates is a fundamental concept of medicinal chemistry. This work has utilised a range of approaches for pharmacophore exploration including scaffold hopping, traditional structure-activity relationships (SARs) and ligand deconstruction/reconstruction to explore candidates targeting TDP-43 and tau. This work has utilised scaffold hopping to undertake structurally significant bioisosteric replacements of reported lead compounds, as well as numerous traditional SAR studies to explore the effect of smaller structural changes on TDP-43 targeting candidates. These compound libraries have been evaluated in a range of cell based TDP-43 proteinopathy models. These evaluations have highlighted the complicated nature of TDP-43 pathology and has emphasised some of the key issues faced throughout central nervous system drug discovery efforts. This work has also identified a selection of compounds that inhibit the formation of pathological tau aggregates in in vitro models. Using an extensive traditional SAR approach, a compound library has been designed and synthesised to refine the active pharmacophore of a hit compound and guide further SAR studies. A selection of these derivatives have been assessed in a disease-relevant tau pathology model. This work has contributed to the wider knowledge base around the development of disease-modifying treatments for neurodegenerative conditions such as AD and FTD.