Design, Synthesis, and Evaluation of a Potent NLRP3 Inflammasome Inhibitor with Favorable Pharmacokinetic and Safety Profiles for Chronic Inflammatory Diseases

Abstract Persistent NLRP3 activation drives chronic inflammatory diseases, necessitating inhibitors with sustained exposure and tolerability. Rational optimization of the hydrophobic and solvent-exposed regions of MCC950 yielded sulfonylurea F34, which inhibited NLRP3-dependent IL-1β release (IC50 = 38.81 nM), with nanomolar potency similar to MCC950, without apparent NLRC4 or AIM2 inhibition. Docking predicted that F34 binds within the MCC950 pocket, where it generally remained during a 200 ns MD simulation. SPR confirmed direct NLRP3 binding (KD = 2.12 μM). In mice, F34 exhibited an oral half-life of 11.89 h and oral bioavailability of 91.36%, potentially contributing to greater efficacy than MCC950 in MSU-induced gouty arthritis and chronic DSS-induced colitis. F34 also showed better tolerability than MCC950 in acute high-dose and 14 day repeated-dose studies, together with weak hERG-channel inhibition (IC50 > 40 μM) and limited CYP inhibition. Thus, optimization preserved nanomolar cellular potency while improving oral exposure, in vivo efficacy, and preliminary tolerability.