Discovery and structure-activity relationship studies of 3-pyridazinesulfonyl derivatives as a new class of inhibitors against NLRP3 inflammasome-dependent pyroptosis.

Inflammatory programmed cell death mediated by NLRP3 inflammasome activation is one of the most representative forms of pyroptosis, involving multiple autoinflammatory diseases. In this investigation, we report the discovery of 3-pyridazinesulfonyl derivatives as a new class of inhibitors against NLRP3 inflammasome-dependent pyroptosis. We initially performed a phenotypic screening against NLRP3-dependent pyroptosis and discovered compound 1 (Hit-1), which showed moderate anti-pyroptotic activity (EC50 = 10.977 ± 2.122 μM). Further structure-activity relationship (SAR) studies resulted in a novel potent compound 32 (N102), which exhibited an EC50 of 0.029 ± 0.010 μM against cell pyroptosis induced by nigericin. N102 displayed remarkable inhibitory activity against NLRP3-dependent activation of caspase-1 and the release of IL-1β in human THP-1 cell-derived macrophages. Mechanistically, N102 disturbed the interaction of NLRP3 with the adaptor protein ASC and inhibited ASC oligomerization. Moreover, N102 possesses favorable HLM stability (T1/2 > 120 min), low CYP3A4 inhibition (IC50 > 10 μM) and good permeability (Papp = 9.063 × 10-5 cm s-1). Overall, we discovered a new potent small molecular inhibitor against NLRP3 inflammasome-dependent pyroptosis with potent cellular activity, favorable human-derived metabolic stability and permeability in vitro, which could be a good lead compound and deserves further in-depth studies.