The
NOD-like receptor pyrin domain-containing
protein 3 (NLRP3)
inflammasome is a multiprotein complex and component of the innate immune system that is activated by exogenous and endogenous danger signals to promote activation of caspase-1 and the maturation and release of the proinflammatory
cytokines interleukin (IL)-1β and
IL-18. Inappropriate activation of NLRP3 has been implicated in the pathophysiology of multiple inflammatory and
autoimmune diseases, including
cardiovascular disease,
neurodegenerative diseases, and
nonalcoholic steatohepatitis (NASH), thus increasing the clinical interest of this target. We describe in this study the preclinical pharmacologic, pharmacokinetic, and pharmacodynamic properties of a novel and highly specific NLRP3 inhibitor,
JT001 (6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonylurea). In cell-based assays,
JT001 potently and selectively inhibited NLRP3
inflammasome assembly, resulting in the inhibition of
cytokine release and the prevention of pyroptosis, a form of inflammatory cell death triggered by active caspase-1.
Oral administration of
JT001 to mice inhibited IL-1β production in peritoneal lavage fluid at plasma concentrations that correlated with mouse in vitro whole blood potency. Orally administered
JT001 was effective in reducing hepatic
inflammation in three different murine models, including the Nlrp3A350V /+CreT model of
Muckle-Wells syndrome (MWS), a diet-induced
obesity NASH model, and a
choline-deficient diet-induced NASH model. Significant reductions in hepatic
fibrosis and cell damage were also observed in the MWS and
choline-deficient models. Our findings demonstrate that blockade of NLRP3 attenuates hepatic
inflammation and
fibrosis and support the use of
JT001 to investigate the role of NLRP3 in other inflammatory disease models. SIGNIFICANCE STATEMENT: Persistent
inflammasome activation is the consequence of inherited mutations of NLRP3 and results in the development of
cryopyrin-associated periodic syndromes associated with severe systemic
inflammation. NLRP3 is also upregulated in
nonalcoholic steatohepatitis, a metabolic chronic
liver disease currently missing a cure. Selective and potent inhibitors of NLRP3 hold great promise and have the potential to overcome an urgent unmet need.