NLRP3 inhibitors(Smith, Gambrell & Russell)

The NLRP3 inflammasome plays a pivotal role in the pathogenesis of acute lung injury (ALI) by regulating pyroptosis, a highly inflammatory form of programmed cell death. NLRP3-mediated pyroptosis leads to alveolar epithelial cell injury, increased pulmonary microvascular endothelial permeability, excessive alveolar macrophage activation, and neutrophil dysfunction, collectively driving ALI progression. In addition to the classical NLRP3-dependent pathway, the non-canonical pyroptosis pathway (caspase-4/5/11) also contributes to ALI by inducing pyroptotic cell death in AECs and ECs, further amplifying NLRP3 activation through damage-associated molecular patterns (DAMP) release. Moreover, neutrophils (NE) pyroptosis exhibits dual roles in ALI, as it enhances pathogen clearance but also exacerbates excessive inflammation and tissue damage, highlighting the complexity of its regulation. Targeting the NLRP3 inflammasome and pyroptotic pathways has emerged as a promising therapeutic strategy for ALI. Various NLRP3 inhibitors (e.g., MCC950, CY-09, OLT1177) and pyroptosis inhibitors have demonstrated significant anti-inflammatory and tissue-protective effects in preclinical models. However, the clinical translation of NLRP3-targeted therapies remains challenging due to off-target effects, potential immunosuppression, lack of patient stratification strategies, and compensatory activation of alternative inflammasomes (e.g., AIM2, NLRC4). Future studies should focus on optimizing the selectivity of NLRP3 inhibitors, developing personalized therapeutic approaches, and exploring combination strategies to enhance their clinical applicability in ALI.

Provided herein are novel compounds as NLRP3 inhibitors, pharmaceutical compositions, use of such compounds in treating asthma or COPD, and processes for preparing such compounds.