ICE/Caspase-1 inhibitors as novel anti-inflammatory drugs.

In recent years, several strategies that selectively inhibit pro-inflammatory cytokines, have yielded effective protein-based therapies for inflammatory disorders, validating the therapeutic hypothesis that intervention in cytokine signalling can provide clinical benefit. However, these protein-based products must be administered by injection, a constraint associated with inconvenience, adverse effects and expense for patients, caregivers and insurers. Besides interfering with the effects of cytokines such as TNF-alpha or IL-1beta that have already been produced, inhibition of pro-inflammatory cytokine production or signalling with low-molecular weight orally-active drugs would combine the convenience of conventional pharmaceuticals with the focused efficacy of the protein therapies. Reducing IL-1beta and IL-18 production by inhibition of IL-1beta converting enzyme (ICE, caspase-1) is one promising strategy because of the key roles of these cytokines in many inflammatory diseases. Pralnacasan, the first orally available, potent and selective ICE inhibitor to enter clinical trials, is currently under investigation in rheumatoid arthritis.