Development of Novel Tetrahydroquinoline Inhibitors of NLRP3 Inflammasome for Potential Treatment of DSS-Induced Mouse Colitis

The NLRP3 inflammasome is a critical
component of innate immunity,
which defends internal and external threats. However, inappropriate
activation of the NLRP3 inflammasome induces various human diseases.
In this study, we discovered and synthesized a series of tetrahydroquinoline
inhibitors of NLRP3 inflammasome. Among these analogues, compound 6 exhibited optimal NLRP3 inhibitory activity. In
vitro studies indicated that compound 6 directly
bound to the NACHT domain of NLRP3 but not to protein pyrin domain
(PYD) or LRR domain, inhibited NLRP3 ATPase activity, and blocked
ASC oligomerization, thereby inhibiting NLRP3 inflammasome assembly
and activation. Compound 6 specifically inhibited the
NLRP3 inflammasome activation, but had no effect on the activation
of NLRC4 or AIM2 inflammasomes. Furthermore, in the dextran sulfate
sodium (DSS)-induced colitis mouse model, compound 6 exhibited
significant anti-inflammatory activity through inhibiting NLRP3 inflammasome in vivo. Therefore, our study provides a potent NLRP3 inflammasome
inhibitor, which deserves further structural optimization as a novel
therapeutic candidate for NLRP3-driven diseases.