ASP-0965

NLRP3 inflammasome inhibitor is a highly attractive drug target for the treatment of various inflammatory diseases. Here, we report the discovery of pyridazine derivatives as a new class of scaffold for NLRP3 inflammasome inhibitors. We optimized HTS hit 2a to improve both in vitro IL-1β inhibitory activity and the mean photo effect (MPE) value in the in vitro 3T3 neutral red uptake (NRU) phototoxicity test. As a result, we identified compound 5e (ASP0965) with brain penetrability and showing efficacy in the brain on oral administration in the rat pharmacodynamics (PD) model and the mouse α-synuclein injection model. These findings suggest that compound 5e is a promising clinical candidate for α-synucleinopathy therapeutics.