Design, Biological Characterization, and Discovery of the Brain-Penetrant NLRP3 Inhibitor Based on a [1,2,4]Triazolo[1,5- a ]pyrimidine Scaffold for the Treatment of Central Nervous System Diseases

NLRP3 inflammasome is a critical cytosolic multiprotein complex central to the innate immune response. Upon activation, NLRP3 oligomerizes and recruits the adapter protein ASC; this scaffold recruits and activates pro-caspase-1. Active caspase-1 catalyzes the proteolytic maturation and secretion of the potent pro-inflammatory cytokines IL-1β and IL-18, and induces a programmed cell death called pyroptosis. Dysregulated or chronic NLRP3 inflammasome activation is a major driver of pathogenesis in a wide spectrum of peripheral inflammatory diseases, including gout, pericarditis, atherosclerosis, nonalcoholic steatohepatitis, and NLRP3 gain-of-function autoinflammatory disorders known as CAPS, as well as neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis. Herein we described the discovery of NLRP3 inhibitors based on the [1,2,4]triazolo[1,5- a ]pyrimidine scaffold. Represented by compound 25, this scaffold exhibited exceptional potency, favorable physicochemical properties, and desirable pharmacokinetic profiles, including good brain penetration. Compound 25 showed potential as a candidate for the treatment of Parkinson’s disease.