Discovery of DA‐7503 as a Novel Tau‐targeted Therapeutic Candidate for the Treatment of Alzheimer’s Disease

Abstract Background Alzheimer’s disease (AD) is a late‐onset, progressive, age‐dependent neurodegenerative disorder. The load of neurofibrillary tangles correlates strongly with clinical progression of the disease. Although tauopathy has been extensively studied as a key hypothesis in AD, there are currently no clinical tau‐targeted drugs that produce a noticeable improvement. Therefore, we studied and developed novel tau‐targeted therapeutic drug candidates for the treatment of AD; in particular, tau aggregation inhibitors. Method We performed high‐content screening based on a Tau‐BiFC cell‐based assay platform and identified novel tau aggregation inhibitors. Lead optimization was subsequently performed to improve potency and ADME/Tox properties, resulting in the production of DA‐7503. In vivo efficacy of the candidate was validated by demonstration of memory impairment restoration in two transgenic animal models of P301L Tau‐BiFC and rTg4510. The non‐clinical GLP‐Tox studies of DA‐7503 is ongoing in order to proceed to clinical studies. Result DA‐7503 exhibited excellent tau aggregation inhibitory activities (cell‐based IC 50 , 0.02 mM, in vitro IC 50 , 0.96 mM) with good cell viability (MTS IC 50 , 77.8 mM). DA‐7503 reduced tau oligomerization and protected against neuronal cell death. It restored memory impairment in P301L Tau‐BiFC and rTg4510 Tg mouse models (NOR, Open Field, and Morris Water Maze test) with reduction of tau pathology. The mode of action of DA‐7503 was confirmed by MALDI‐TOF Mass Spectrometric Analysis, 2D HSQC NMR and TR‐2 competition study to show reversible covalent inhibition of disulfide‐dependent oligomer formation. Conclusion DA‐7503 , a highly potent inhibitor of tau aggregation, significantly improved memory impairment and reduced tau pathology in P301L Tau‐BiFC and rTg4510 Tg mouse models with good pharmacological properties. Currently, the GLP‐Tox safety profile of DA‐7503 as a non‐clinical candidate is being evaluated, and early results are promising enough to proceed to clinical studies.