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

Abstract

Targeting NLRP3 inflammasome with inhibitors is a novel strategy for NLRP3-driven diseases. Herein, hit compound <b>5</b> possessing an attractive skeleton was identified from our in-house database of oridonin, and then a potential lead compound <b>32</b> was obtained by optimization of <b>5</b>, displaying two-digit nanomolar inhibition on NLRP3. Moreover, compound <b>32</b> 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 <b>32</b> without altering NLRC4 or AIM2 inflammasome. Crucially, compound <b>32</b> 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.