Belnacasan (VX765)

Description: Belnacasan (also known as VX-765) is a novel, potent, selective and orally bioactive prodrug of VRT-043198 which is a potent and selective inhibitor of caspase-1 with Ki values of 0.8 nM and less than 0.6 nM for caspase-1 and caspase-4, respectively. Belnacasan exhibits potent anti-inflammatory activities by inhibiting the release of IL-1beta and IL-18. Caspase-1 belongs to the IL-converting enzyme (ICE)/caspase-1 sub-family caspases. VX-765 is usually metabolized to an active molecular VRT-043198. In cultures of peripheral blood mononuclear cells stimulated with bacterial products, VRT-043198 inhibited the release of Interleukin (IL)-1beta and IL-18, but had no affect the secretion of other cytokines such as IL-alpha, TNFalpha, IL-6 and IL-8. This product is also used in other models to illustrate the function of Caspase-1.

References:

1. Cell Death Dis. 2012 Jul 5; 3:e338;

2. Stack JH, et al. IL-converting enzyme/caspase-1 inhibitor VX-765 blocks the hypersensitive response to an inflammatory stimulus in monocytes from familial cold autoinflammatory syndrome patients. J Immunol. 2005 Aug 15; 175(4):2630-4;

3. Wannamaker W, 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.