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

• DOI: 10.48550/arxiv.2309.07939
• Publication Date: 2023-01-01
• Authors: Simone Gastaldi; Carmine Rocca; Eleonora Gianquinto; Maria Concetta Gr...; Valentina Boscaro; Federica Blua; Barbara Rolando; Elisabetta Marini; Margherita Gallic...; Anna De Bartolo; Naomi Romeo; Rosa Mazza; Francesco Fedele; Pasquale Pagliaro; Cláudia Penna; Francesca Spyrakis; Massimo Bertinaria; Tommaso Angelone
• Keywords: Sulfonylurea

Inspired by the recent advancements in understanding binding mode of sulfonylurea-based NLRP3 inhibitors to sensor protein, we developed new replacing central sulfonylurea moiety with different heterocycles. Computational studies evidenced that some designed compounds were able maintain important interaction within NACHT domain target protein similarly most active inhibitors. Among studied compounds, 1,3,4-oxadiazol-2-one derivative 5 (INF200) showed promising results being prevent NLRP3-dependent pyroptosis triggered LPS/ATP and LPS/MSU 66.3 +/- 6.6% 61.6 11.5% reduce IL-1\b{eta} release (35.5 8.8 % {\mu}M) at 10 {\mu}M human macrophages. The selected compound INF200 (20 mg/kg/day) was then tested an vivo rat model high-fat diet (HFD)-induced metaflammation evaluate its beneficial cardiometabolic effects. significantly counteracted HFD-dependent "anthropometric" changes, improved glucose lipid profiles, attenuated systemic inflammation biomarkers cardiac dysfunction (particularly BNP). Hemodynamic evaluation on Langendorff indicate limited myocardial damage-dependent ischemia/reperfusion injury (IRI) improving post-ischemic systolic recovery attenuating contracture, infarct size, LDH release, thus reversing exacerbation obesity-associated damage. Mechanistically, hearts, IFN200 reduced IRI-dependent activation, inflammation, oxidative stress. These highlight potential novel inhibitor, INF200, ability reverse unfavorable cardio-metabolic associated obesity.