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

In recent years, several strategies that selectively inhibit pro-inflammato ry cytokines, have yielded effective protein-based therapies for inflammato ry disorders, validating the therapeutic hypothesis that intervention in cy tokine signalling can provide clinical benefit. However, these protein-base d products must be administered by injection, a constraint associated with inconvenience, adverse effects and expense for patients, caregivers and ins urers. Besides interfering with the effects of cytokines such as TNF-alpha or IL-1 beta that have already been produced, inhibition of pro-inflammator y cytokine production or signalling with low-molecular weight orally-active drugs would combine the convenience of conventional pharmaceuticals with t he focused efficacy of the protein therapies. Reducing IL-1 beta and IL-18 production by inhibition of IL-1 beta 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 inves tigation in rheumatoid arthritis.