VRT-043198, the drug metabolite of VX-765 (Belnacasan), is a potent, selective and blood-brain barrier permeable inhibitor of interleukin-converting enzyme/caspase-1 subfamily caspases. VRT-043198 exhibits Ki values of 0.8 nM and 0.6 nM for ICE/caspase-1 and caspase-4, respectively.IC50 & Target: Ki: 0.8 nM (caspase-1) and 0.6 nM (caspase-4).In Vitro: VRT-043198 exhibits 100- to 10,000-fold selectivity against other caspase-3 and -6 to -9.
VRT043198 inhibits the release of interleukin (IL)-1β and IL-18, but it has little effect on the release of several other cytokines, including IL-1α, tumor necrosis factor-, IL-6 and IL-8. VRT-043198 inhibited IL-1β release from both PBMCs (n = 8) and whole blood (n = 4) with IC50 values of 0.67±0.55 and 1.9±0.80 nM, respectively.
VRT-043198 lacks potent antiapoptotic activity.
In Vivo: VX-765 is converted rapidly to VRT-043198 under the action of plasma and liver esterases and also much more slowly in aqueous solution.
VX765 reduces disease severity and the expression of inflammatory mediators in models of rheumatoid arthritis and skin inflammation.
VX765 (25, 50, 100, or 200 mg/kg) inhibits lipopolysaccharide-induced cytokine secretion.