[P4–589]: CNS DRUG‐LIKE INHIBITORS OF TAU OLIGOMERIZATION

Tau oligomers form in neurons as tau redistributes from the axon to the cell body when tau protein loses its affinity to microtubules due to hyperphosphorylation during Alzheimer's disease and related tauopathies. Tau oligomers can accumulate in both the intracellular and extracellular spaces and have been shown to be toxic to neurons, reduce long-term potentiation (LTP) in mouse hippocampal slices, impair memory formation in wild type (w.t.) mice, and transmit tau pathology to neighboring neurons. Hence, tau oligomers have become a target for drug discovery using small molecule and antibody based approaches. Assays have been developed and used to select and optimize small molecules that inhibit tau monomer self-association. Here, we compare the chemical properties of our lead series to approved CNS drugs and other published molecules targeting tau. We also highlight in vivo studies testing the pharmacokinetics (PK) and safety of our lead compounds. The chemical properties of the molecules were compared based on their molecular weight, log of the partition coefficient (logP), polar surface area (PSA), and number of hydrogen bond donors and acceptors using graphical statistical software. PK analysis of plasma/brain compound levels was performed in mice. Compound safety was evaluated in a 5-day study in w.t. mice at 100 mg/kg using oral administration. The chemical profile of our lead series was more similar to that of FDA approved CNS drugs compared to tau aggregation inhibitors selected using tau fibril formation assays. Further, pharmacokinetic analyses showed that one of our lead series compounds readily penetrates the blood-brain-barrier. Our screening approach has enabled the selection of CNS drug-like molecules based on their chemical properties, and our lead compound showed CNS drug-like properties in mouse PK and safety studies. Targeting tau monomer self-association yields molecules with better CNS drug-like properties than published molecules selected using tau fibril formation assays.