Discovery of novel and potent NLRP3 inflammasome inhibitors with new lipophilic moieties.

The NLRP3 inflammasome plays a pivotal role in innate immunity by triggering caspase-1 mediated release of the pro-inflammatory cytokines IL-1β and IL-18. These cytokines are implicated in various inflammatory and metabolic disorders, including Cryopyrin-Associated Periodic Syndromes (CAPS), gouty arthritis, obesity and cardiovascular diseases. In this study, we report the discovery and synthesis of a novel non-tricyclic series of NLRP3 inhibitors. Among them, the representative compound 32 bearing 3-(1-cyclopropylethyl)bicyclo[4.2.0]octa-1(6),2,4-triene motif was identified with improved potency and enhanced drug-like properties compared to MCC950. Key optimization strategies included exploring hydrophobic interactions with new moieties, achieving a balance between potency and lipophilicity, and improving physicochemical properties as well as in vitro and in vivo pharmacokinetics. Compound 32 demonstrated significant in vivo efficacy in acute peritonitis model, highlighting its therapeutic potential for inflammatory diseases.