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Inspired by the recent advancements in understanding the binding mode ofsulfonylurea-based NLRP3 inhibitors to the NLRP3 sensor protein, we developednew NLRP3 inhibitors by replacing the central sulfonylurea moiety withdifferent heterocycles. Computational studies evidenced that some of thedesigned compounds were able to maintain important interaction within the NACHTdomain of the target protein similarly to the most active sulfonylurea-basedNLRP3 inhibitors. Among the studied compounds, the 1,3,4-oxadiazol-2-onederivative 5 (INF200) showed the most promising results being able to preventNLRP3-dependent pyroptosis triggered by LPS/ATP and LPS/MSU by 66.3 +/- 6.6%and 61.6 +/- 11.5% and to reduce IL-1\b{eta} release (35.5 +/- 8.8 % {\mu}M) at10 {\mu}M in human macrophages. The selected compound INF200 (20 mg/kg/day) wasthen tested in an in vivo rat model of high-fat diet (HFD)-inducedmetaflammation to evaluate its beneficial cardiometabolic effects. INF200significantly counteracted HFD-dependent "anthropometric" changes, improvedglucose and lipid profiles, and attenuated systemic inflammation and biomarkersof cardiac dysfunction (particularly BNP). Hemodynamic evaluation onLangendorff model indicate that INF200 limited myocardial damage-dependentischemia/reperfusion injury (IRI) by improving post-ischemic systolic recoveryand attenuating cardiac contracture, infarct size, and LDH release, thusreversing the exacerbation of obesity-associated damage. Mechanistically, inpost-ischemic hearts, IFN200 reduced IRI-dependent NLRP3 activation,inflammation, and oxidative stress. These results highlight the potential ofthe novel NLRP3 inhibitor, INF200, and its ability to reverse the unfavorablecardio-metabolic dysfunction associated with obesity.

Discovery of a novel 1,3,4-oxadiazol-2-one-based NLRP3 inhibitor as a  pharmacological agent to mitigate cardiac and metabolic complications in an  experimental model of diet-induced metaflammation