Novel irreversible caspase-1 inhibitor attenuates the maturation of intracellular interleukin-1beta.

Caspase-1, the most efficient enzyme in processing the proinflammatory cytokines interleukin 1beta and interleukin 18 in humans, is associated with inflammatory diseases such as rheumatoid arthritis, osteoarthritis, and some neuronal diseases. We previously reported that isoquinoline-1,3,4-trione and its derivatives are novel caspase-3 inhibitors that could attenuate apoptosis in vitro and in vivo. Here we report a novel derivative of isoquinoline-1,3,4-trione that is highly potent in inhibiting caspase-1 activity in an irreversible and slow-binding manner, thus inhibiting cellular caspase-1 activity and the maturation of interleukin 1beta in U-937 cells.