Potent Non-Covalent Inhibitors of Caspase-1 Targeting Neuroinflammation in Neurodegenerative Diseases

Recent studies have shown the pivotal role of innate immune activation in the pathogenesis of major neurodegenerative diseases. It has been discovered that microglia and other cell of the brain innate immune system, may be activated by misfolded proteins or aberrant endogenous molecular patterns that are accumulated in the brain of patients affected by several neurodegenerative disorders. These stimuli are responsible for chronic neuroinflammation by triggering the inflammasome's formation and subsequent caspase-1 activation. Proinflammatory cytokines are processed by active caspase-1 into their mature form leading to cytokines production and, ultimately, chronic inflammation. Furthermore, the extensive generation of proinflammatory cytokines (IL-1?, IL-18) mediated from activated caspase-1, leads to pyroptosis that plays an important role in several neurological diseases. Moreover, recent findings indicate caspase-1 as a modulator for the activation of caspase-6 mediated axonal degeneration in AD. There is evidence that caspase-1 inhibition might effectively interfere with the onset and progression of neurological disorders. We have designed and synthesized new potent and selective non-peptidic, non-covalent, cell permeable caspase-1 inhibitors, which have shown a very high activity in suppressing the formation of IL-1? in LPS induced inflammation and to cross the BBB in PET experiments.