VRT-043198, the agent 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 K i values of 0.8 nM and 0.6 nM for ICE/caspase-1 and caspase-4, respectively
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 IC 50 values of 0.67±0.55 and 1.9±0.80 nM, respectively. VRT-043198 lacks potent antiapoptotic activity. MCE has not independently confirmed the accuracy of these methods. They are for reference only.
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 . MCE has not independently confirmed the accuracy of these methods. They are for reference only. Animal Model: Naïve male CD-1 mice . Dosage: 25-200 mg/kg. Administration: Oral gavage 1 h before i.v. injection of 2 mg/kg E. coli LPS (strain 0111:B4). Result: Reduced serum IL-1β levels.
