Succinamide inhibitors of IL-1β converting enzyme

Abstract

Succinamide derivatives containing a modified aspartate moiety are claimed as inhibitors of caspase-1 (IL-1β converting enzyme [ICE]). Other claims include pharmaceutical compositions of these compounds and their use for the treatment of disorders in which caspase-1 is thought to be involved (e.g., stroke, inflammatory diseases, septic shock, reperfusion injury, Alzheimer’s disease, shigellosis and multiple sclerosis). The compounds are assayed against caspase-1 in a colourimetric assay to afford K_iand IC₅₀ values, with the most potent compound showing a K_ivalue of 0.4 nM. In an analogous way the inhibitory activity against caspase-4 (Ich-2) was determined. The ability of the compounds to inhibit IL-1β production has been examined in an assay containing human peripheral blood mononuclear cells (PBMCs) stimulated by lipopolysaccharide (LPS). The viability of the cells was determined by an MTT assay but no results were presented.

• Alzheimer's disease
• arthritis
• caspase-1
• cerebrovascular ischaemia
• ICE inhibitors
• IL-1beta
• inflammatory bowel disease
• multiple sclerosis
• septic shock
• shigellosis
• stroke
• succinamide