A new class of non-covalent caspase-1 inhibitors. The synthesized low molecular weight non-peptidic molecules have shown neuroprotective activity and are able to cross the blood brain barrier. Such molecules are of interest to modulate the inflammatory process with potential therapeutic application for both acute and chronic neurodegenerative diseases but also for inflammatory based diseases as articular diseases, skin disorders, and bowel diseases.
It is well established the central role of the innate immune system activation in the onset and progression of many neurodegenerative diseases. Misfolded proteins located in the brain of patients suffering from these diseases are able to activate microglia causing a chronic neuroinflammation process via activation of inflammasome and capsasi-1. Caspase-1 then regulates the inflammatory process transforming proIL-1β and proIL-18 in their biologically active mature form. Several evidence demonstrate that inhibition of caspase-1 controls the inflammatory process and related conditions. Although several covalent caspase-1 inhibitors have been discovered none of these has passed the clinical trials because of toxicity problems, probably due to the high reactivity of their electrophilic portion P1. The discovery of new non-covalent caspase-1 inhibitors may overcome these drawbacks, and could permit the therapeutic application of caspase-1 inhibitors.