Hit-to-Lead Optimization of the Natural Product Oridonin as Novel NLRP3 Inflammasome Inhibitors with Potent Anti-Inflammation Activity

Targeting NLRP3 inflammasome with inhibitors is a novel
strategy
for NLRP3-driven diseases. Herein, hit compound 5 possessing
an attractive skeleton was identified from our in-house database of
oridonin, and then a potential lead compound 32 was obtained
by optimization of 5, displaying two-digit nanomolar
inhibition on NLRP3. Moreover, compound 32 showed enhanced
safety index (SI) relative to oridonin (IC50 = 77.2 vs
780.4 nM, SI = 40.5 vs 8.5) and functioned through blocking ASC oligomerization
and interaction of NLRP3-ASC/NEK7, thereby suppressing NLRP3 inflammasome
assembly and activation. Furthermore, diverse agonists-induced activations
of NLRP3 could be impeded by compound 32 without altering
NLRC4 or AIM2 inflammasome. Crucially, compound 32 possessed
tolerable pharmaceutical properties and significant anti-inflammatory
activity in MSU-induced gouty arthritis model. Therefore, this work
enriched the SAR of NLRP3 inflammasome inhibitors and provided a potential
candidate for the treatment of NLRP3-associated diseases.