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 Ki values of 0.8 nM and 0.6 nM for ICE/caspase-1 and caspase-4, respectively[1].

Signaling Pathways >> Apoptosis >> Caspase

Research Areas >> Inflammation/Immunology

Caspase-1:0.8 nM (Ki)

Caspase-4:0.6 nM (Ki)

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].

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]. Animal Model: Naïve male CD-1 mice[1]. 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.

[1]. Woods Wannamaker, et al. (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-1beta and IL-18. J Pharmacol Exp Ther. 2007 May;321(2):509-16.