Design and synthesis of INF195, a new NLRP3 Inflammasome Inhibitor with ex vivo cardioprotective effect

The NLRP3 inflammasome, a cytosolic multi protein complex involved in inflammatory processes, is emerging in the myocardial ischemia-reperfusion injury (IRI) framework, being engaged in both cell survival and damage [1-3]. In the search for novel NLRP3 inhibitors, we designed a series of compounds with the help of molecular docking techniques. The activity of the compounds was evaluated in vitro in human macrophages. One compound, INF195, was selected to investigate the cardioprotective properties [4]. We measured infarct size (IS) in isolated mouse hearts exposed to 30-minute global ischemia and then one-hour reperfusion, either in the absence or presence of different doses of INF195 (5, 10 or 20 µM). We also evaluated the production of the markers of NLRP3 activation, caspase-1 and IL-1β, measuring their concentrations in cardiac tissue homogenates. The results infer that heart pre-treatment with low doses of INF195, 5 and 10 µM, considerably reduce IS and IL-1β production, suggesting therefore that the activation of NLRP3 expressed in myocardial cells plays a role in IRI. Moreover, INF195 at low doses significantly reduced the infarcted area (the infusion at 5µM reduced IS from 64.8±1.9% to 38.1±1.3%). Overall, INF195 showed a promising cardioprotective effect worth of further studies.