NLRP3 inflammasomes have recently emerged as an attractive drug target for neurodegenerative disorders. In our continuing studies, a new chemical scaffold was designed as selective inhibitors of NLRP3 inflammasomes. Initial characterization of the lead HL16 demonstrated improved, however, nonselective inhibition on the NLRP3 inflammasome. Structure-activity relationship studies of HL16 identified a new lead, 17 (YQ128), with an IC50 of 0.30 ± 0.01 μM. Further studies from in vitro and in vivo models confirmed its selective inhibition on the NLRP3 inflammasome and its brain penetration. Furthermore, pharmacokinetic studies in rats at 20 mg/kg indicated extensive systemic clearance and tissue distribution, leading to a half-life of 6.6 h. However, the oral bioavailability is estimated to be only 10%, which may reflect limited GI permeability and possibly high first-pass effects. Collectively, these findings strongly encourage development of more potent analogues with improved pharmacokinetic properties from this new chemical scaffold.