Design, synthesis and biological evaluation of 1,5-disubstituted aamino tetrazole derivatives as non-covalent inflammasome-caspase-1 complex inhibitors with potential application against immune and inflammatory disorders

Compounds targeting the inflammasome-caspase-1 pathway could be of use for the treatment ofinflammation and inflammatory diseases. Previous caspase-1 inhibitors were in great majority covalentinhibitors and failed in clinical trials. Using a mixed modelling, computational screening, synthesis andin vitro testing approach, we identified a novel class of non-covalent caspase-1 non cytotoxic inhibitorswhich are able to inhibit IL-1b release in activated macrophages in the low mM range, in line with thebest activities observed for the known covalent inhibitors. Our compounds could form the basis offurther optimization towards potent drugs for the treatment of inflammation and inflammatory disordersincluding also dysregulated inflammation in Covid 19.