Description
VX-765 can inhibit capase-1 with Ki of 0.8 nM.
Storage
2 years at -20 centigrade
Molecular Formula
C24H33ClN4O6
Chemical Name
(S)-1-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanoyl)-N-((2R,3S)-2-ethoxy-5-oxo-tetrahydrofuran-3-yl)pyrrolidine-2-carboxamide
Solubility
DSMO Water Ethanol
In vitro
VX-765 can inhibit capase-1 with Ki of 0.8 nM. As an orally active IL-converting enzyme/caspase-1 inhibitor, VX-765 blocks IL-1beta secretion with equal potency in LPS-stimulated cells from FCAS ( Familial cold autoinflammatory syndrome). VX-765 is an orally absorbed prodrug of VRT-043198. VRT-043198 is a potent and selective inhibitor of interleukin-converting enzyme/caspase-1 subfamily caspases. And VRT-043198 exhibits 100- to 10,000-fold selectivity against other caspase-3 and caspase-6 to caspase-9. VRT-043198 inhibits the release of interleukin (IL)-1beta and IL-18, but it had little effect on the release of several other cytokines, including IL 1alpha, tumor necrosis factor-alpha, IL-6 and IL-8. But 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.
In vivo
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. 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.
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