Discovery of Second-Generation NLRP3 Inflammasome Inhibitors: Design, Synthesis, and Biological Characterization

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.