Non-covalent inflammasome-caspase-1 complex inhibitors: New molecules targeting immune and inflammatory disorders including COVID-19

There is a growing evidence of the relation between an excessive release of pro-inflammatory IL-1beta triggered by the inflammasome-caspase 1 complex, and various immune and inflammatory disorders, including CNS diseases such as Alzheimer's (AD), Parkinson’s (PD) and Huntington's (HD) diseases, amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Moreover, there is also a growing evidence that the pathway inflammasome NLRP3/caspase-1 is overactivated by the SARS-Cov-2 and may be responsible for the high mortality observed in the COVID-19 patients due to the inflammatory internal organs collapse driven by the cytokine storm induced by the virus. It is now quite clear that an effective pharmacological approach to Covid-19 must comprise an antiviral drug in combination with an inflammation modulator able to regulate the innate immunity system response preserving its regular activity but quenching its overactivation. For all of these reasons a new caspase-1 inhibitor drug could be a useful tool to treat inflammation driven diseases including Covid-19.
For this purpose, we have designed a new class of non-covalent, non-peptidic, small molecule caspase-1 inhibitors through structure-based drug design. The multicomponent reaction approach allows the straightforward synthesis of the desired compounds, offering a significant advantage over conventional linear step synthesis by permitting the one pot assembly of very complex structures. This new class of inhibitors shows an IC₅₀ in the low micromolar range, and could be further optimized towards new inflammasome/caspase-1 pathway inhibitors characterized by high bioavailability, potency and reduced toxicity.