(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), an orally available selective interleukin (IL)-converting enzyme/caspase-1 inhibitor, exhibits potent anti-inflammatory activities by inhibiting the release of IL-1β and IL-18

S)- 1-(( S)- 2-{[ 1-( 4- Amino- 3- chloro- phenyl)- methanoyl]- amino}3,3- dimethyl- butanoyl)- pyrrolidine- 2- carboxylic acid (( 2R, 3S)- 2ethoxy- 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- 2yl]- 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, VRT043198 inhibited the release of interleukin ( IL)- 1 beta and IL-18, but it had little effect on the release of several other cytokines, including IL-1 alpha, tumor necrosis factor-alpha, 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, VX765 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.