Discovery of novel hydroxime-based NLRP3 inflammasome inhibitors with reduced hepatotoxicity

The NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome plays a critical role in mediating intracellular caspase-1 activation, IL-1β release, and pyroptosis with its excessive activation being closely associated with the pathogenesis of various inflammatory diseases. In this study, a series of novel hydroxime-based NLRP3 inflammasome inhibitors were designed and synthesized. Among them, compound ZM734 exhibited potent inhibitory activity against IL-1β secretion in mouse bone marrow-derived macrophages (BMDMs). In addition, compound ZM734 effectively inhibited NLRP3 inflammasome activation induced by diverse stimuli. Compound ZM734 demonstrated a definite protective effect and was capable of alleviating pulmonary inflammation in a C57BL/6 mouse model of acute lung injury. Notably, the cytotoxicity of compound ZM734 toward human hepatic stellate LX-2 cells was significantly reduced. Furthermore, the increases in serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in mice treated with compound ZM734 at the same dose were significantly lower than that of MCC950. These findings thereby provide a new direction to the further structural optimization for the discovery of low toxicity NLRP3 inflammasome inhibitors.