VRT-043198

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 K_i values of 0.8 nM and 0.6 nM for ICE/caspase-1 and caspase-4, respectively^[1]. IC50 & Target: Ki: 0.8 nM (caspase-1) and 0.6 nM (caspase-4)^[1]. In Vitro: VRT-043198 exhibits 100- to 10,000-fold selectivity against other caspase-3 and -6 to -9^[1].
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^[1].
VRT-043198 lacks potent antiapoptotic activity^[1].
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^[1].
VX765 reduces disease severity and the expression of inflammatory mediators in models of rheumatoid arthritis and skin inflammation^[1].
VX765 (25, 50, 100, or 200 mg/kg) inhibits lipopolysaccharide-induced cytokine secretion^[1].