(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

Abstract

(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

Inflammasome-independent Role of Apoptosis-associated Speck-like Protein Containing a CARD (ASC) in T Cell Priming Is Critical for Collagen-induced Arthritis

“…Our observation that caspase-1-deficient mice are susceptible to CIA may appear as a contradiction to a previous report demonstrating that the chemical Casp1 inhibitor VX-765 provided protection against CIA (20). However, it should be noted that VX-765 is also an effective inhibitor of other inflammatory caspases.…”

“…The Induction of Humoral Immunity during Collagen-induced Arthritis Requires ASC, but Not Nlrp3 or Caspase-1-Both T cellmediated and humoral immune responses have been demonstrated to play an essential role in the pathogenesis of CIA (3)(4)20). To gain some insight into the mechanism by which ASC mediates CIA, we first determined the serum levels of CIIspecific antibodies in immunized mice at day 42 post-immunization.…”

Reducing C-terminal truncation mitigates synucleinopathy and neurodegeneration in a transgenic model of multiple system atrophy

“…Such difference was also found for IL-1β levels, as VX-765 only decreased IL-1β levels in the striatum but not in the cortex. VX-765 is an inhibitor of caspase-1, the primary cleaving and activating mechanism of IL-1β from its precursor, pro-IL-1β (17)(18)(19). These results further support the hypothesis that the effects of VX-765 in the brain are structure and region dependent.…”

“…Therefore, VX-765 could exert neuroprotective effects on MSA pathogenesis by reducing α-syn cleavage, hence limiting its toxicity and its ability to form aggregates. VX-765 is an orally active, well-tolerated, brain-penetrant prodrug that is hydrolyzed by esterases in vivo to produce a potent and selective caspase-1 inhibitor (17,18), an activity supported by the in vivo demonstration of reduced cleavage of pro-Interleukin-1β (IL-1β) to its activated form IL-1β, a proinflammatory process under control of caspase-1 (18)(19)(20).…”

Overexpression of the Dominant-Negative Form of Interferon Regulatory Factor 1 in Oligodendrocytes Protects against Experimental Autoimmune Encephalomyelitis

“…Detailed examinations of MS pathological specimens have demonstrated that oligodendrocyte injury and apoptosis can be accompanied by limited inflammation and may, in fact, represent the initial event of lesions formation (Lucchinetti et al, 2000;Barnett and Prineas, 2004). Therefore, exploring oligodendrocyte-related pathogenic mechanisms, in addition to the conventional immune-based ones, can be of independent therapeutic significance in MS. Perhaps targeting IRF-1 and Caspase 1 signaling by pharmaceutical agents can be of clinical utility in controlling the disease activity in MS (Lin and Hiscott, 1999;Wannamaker et al, 2007). Interferon-␤, a MS therapeutic and a strong inducer of IRF-1 expression, has been reported to exert a harmful effect on oligodendrocytes (Taniguchi et al, 2001;Heine et al, 2006;Trebst et al, 2007).…”