Discovery of\nNP3-253, a Potent Brain Penetrant Inhibitor\nof the NLRP3 Inflammasome

Activation of the NLRP3 inflammasome in response to danger\nsignals\nis a key innate immune mechanism and results in the production of\nthe pro-inflammatory cytokines interleukin-1β (IL-1β)\nand interleukin-18 (IL-18) as well as pyroptotic cell death. Aberrant\nNLRP3 activation has been linked to many acute and chronic conditions\nranging from atherosclerosis to Alzheimer’s disease and cancer,\nand based on the clinical success of IL-1-targeting therapies, NLRP3\nhas emerged as an attractive therapeutic target. Herein we describe\nour discovery, characterization, and structure-based optimization\nof a pyridazine-based series of NLRP3 inhibitors initiating from an\nhigh-throughput screening campaign. The scaffold, exemplified by lead\nmolecule <b>NP3-253</b>, has excellent potency and physicochemical\nand pharmacokinetic properties, including good brain penetration.\nThe establishment of pharmacokinetic/pharmacodynamic relationships\nin the periphery and central nervous system in mechanistic models\nfacilitates the use of <b>NP3-253</b> as a tool to further interrogate the biology of NLRP3 in peripheral\nand neuroinflammatory models.