(S)-1-((S)-2-{[1-(4-Amino-3-chloro-phenyl)-methanoyl]-amino}-3,3-dimethyl-butanoyl)-pyrrolidine-2-carboxylic acid ((2R,3S)-2-ethoxy-5-oxo-tetrahydro-furan-3-yl)-amide (VX-765) is an orally absorbed prodrug of (S)-3-({1-[(S)-1-((S)-2-{[1-(4-amino-3-chlorophenyl)-methanoyl]-amino}-3,3-dimethyl-butanoyl)-pyrrolidin-2-yl]-methanoyl}-amino)-4-oxo-butyric acid (VRT-043198), a potent and selective inhibitor of interleukin-converting enzyme/ caspase-1 subfamily caspases. VRT-043198 exhibits 100-to 10,000-fold selectivity against other caspase-3 and -6 to -9. The therapeutic potential of VX-765 was assessed by determining the effects of VRT-043198 on cytokine release by monocytes in vitro and of orally administered VX-765 in several animal models in vivo. In cultures of peripheral blood mononuclear cells and whole blood from healthy subjects stimulated with bacterial products, VRT-043198 inhibited the release of interleukin (IL)-1␤ and IL-18, but it had little effect on the release of several other cytokines, including IL-1␣, tumor necrosis factor-␣, IL-6 and IL-8. In contrast, VRT-043198 had little or no demonstrable activity in cellular models of apoptosis, and it did not affect the proliferation of activated primary T cells or T-cell lines. VX-765 was efficiently converted to VRT-043198 when administered orally to mice, and it inhibited lipopolysaccharide-induced cytokine secretion. In addition, VX-765 reduced disease severity and the expression of inflammatory mediators in models of rheumatoid arthritis and skin inflammation. These data suggest that VX-765 is a novel cytokine inhibitor useful for treatment of inflammatory diseases.The interleukin-converting enzyme (ICE), also known as caspase-1, is the cysteine protease that cleaves pro-interleukin (IL)-1␤ and pro-IL-18 to form the mature, active cytokines IL-1␤ and IL-18, respectively. IL-1␤ and IL-18 have important roles in the acute and chronic stages of inflammatory immune responses (for review, see Braddock and Quinn, 2004). IL-1␤ induces the expression of several mediators of immune cell response, including tumor necrosis factor (TNF)-␣, IL-6, cyclooxygenase-2, chemokines, Article, publication date, and citation information can be found at