Protein misfolding and aggregation comprise the underlying common pathological mechanism of many neurodegenerative disorders. In the case of tauopathies, a group of neurodegenerative diseases, which include Alzheimer's disease, the aggregation of the microtubule-associated protein tau is believed to have pathological consequences via toxic gains and/or losses of functions. Tau is an endogenous MT-stabilizing agent that is highly expressed in the axons of neurons. The MT-stabilizing function of tau is essential for the axonal transport of proteins, neurotransmitters and other essential cellular constituents. Under pathological conditions, tau misfolding and aggregation results in axonal transport deficits that appear to have deleterious consequences for the affected neurons, leading to synapse dysfunction and, ultimately, neuronal loss. As such, agents capable of preventing the misfolding and aggregation of tau hold considerable promise for the prevention and/or treatment of these serious diseases. We have recently identified a novel class of tau aggregation inhibitors, the aminothienopyridazines, which exhibit highly promising combinations of biological activity as well as drug-like properties (see Biochemistry 2009, 48, 32, 7732-45). The objective of this Proposal is to conduct a medicinal chemistry optimization program with the goal of identifying candidates that would be appropriate for efficacy studies in animal models of human tauopathies.