Belnacasan | ICE/caspase-1 inhibitor

Belnacasan (273404-37-8) is a prodrug of VRT-043198, a potent (Ki = 0.8 nM ICE/caspase-1; <0.6nM caspase-4) and selective inhibitor of interleukin-converting enzyme/caspase-1 subfamily caspases.¹ VRT-043198 ICE/caspase-1 IC₅₀ = 0.67 µM PBMCs, 1.0 µM whole blood.  It inhibited the release of IL-1b and IL-18 from human monocytes in vitro and their production in vivo in models of inflammation. Belnacasan inhibited the activation and expression of the NLRP3 Inflammasome leading to moderation of depressive-like behaviors induced by chronic mild stress² and prevention of glial pyroptosis in multiple sclerosis models³. It inhibited pyroptosis in vascular smooth muscle cells during atherogenesis suggesting a possible therapeutic effect in treating atherosclerotic disease.⁴ Belnacasan reduced acute seizures and drug resistant chronic epileptic activity in mice⁵ and provided neuroprotection in two rat models of temporal lobe epilepsy⁶.  It also displays protective effects in models of stroke⁷and Alzheimer’s disease⁸.

References:

1. Wannamaker et al. (2007)(S)-1-((S)-2-{[1-(4-Amino-3-chlorophenyl)-methanoyl]-amino}-3,3-dimethylbutanoyl)-pyrrolidine-2-carboxylic acid ((2R,3S)-2-ethoxy-5-oxotetrahydrofuran-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-1b and IL-18, J. Pharmacol. Exp. Ther. 321 509
2. Zhang et al. (2015) NLRP3 Inflammasome Mediates Chronic Mild Stress-Induced Depression in Mice via Neuroinflammation, J. Neuropsychopharmacol. 18 pyv006
3. McKenzie et al. (2018) Caspase-1 inhibition prevents glial inflammasome activation and pyroptosis in models of multiple sclerosis, Proc. Natl. Acad. Sci USA 115 E6065
4. Li et al. (2020) VX-765 attenuates atherosclerosis in ApoE deficient mice by modulating VSMCs pyroptosis, Exp. Cell Res. 389 111847
5. Maroso et al. (2011) Interleukin-1b biosynthesis inhibition reduces acute seizures and drug resistant chronic epileptic activity in mice, Neurotherapeutics 8 304
6. Noe et al. (2013) Pharmacological blockade of IL-1b/IL-1 receptor type 1 axis during epileptogenesis provides neuroprotection in two rat models of temporal lobe epilepsy, Neurobiol. Dis. 59 183
7. Li et al. (2019) Caspase-1 inhibition mediates neuroprotection in experimental stroke by polarizing M2 microglia/macrophage and suppressing NF-kB activation, Biochem. Biophys. Res. Commun. 513 479
8. Flores et al. (2018) Caspase-1 inhibition alleviates cognitive impairment in an Alzheimer’s disease mouse model, Nat. Commun. 9 3916