(S)-1-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanoyl)-N-((2R,3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)pyrrolidine-2-carboxamide

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.

VX-765 shows anti-convulsant activity by inhibiting interlukin-1β biosynthesis.

ChEBI: Belnacasan is a dipeptide.

The cell-permeable prodrug of the caspase-1/4-selective inhibitor VRT-43198 (K_i in nM = <0.6/Caspase-4, 0.8/Caspase-1, 100/Caspase-8, 560/Caspase-6, 1,030/Caspase-9, 9,000/Granzyme B, 16,000/Caspase-7, 21,500/Caspase-3; IC₅₀ >100 μM against Cathepsin B & Trypsin). In addition to inhibiting LPS-induced IL-1β production in primary human PBMC cultures (IC₅₀ ~1 μM), VX-765 is also effective in preventing HIV infection-induced IL-1β production and pyroptosis of CD4 T cells in human lymphoid aggregate cultures (HLAC; CD4 population = 29.2% in non-infected control cultures, 8.3% vs. 30.2% in infected cultures with or without 5 μM VX-765). VX-765 is orally available in mice (Blood C_max = 0.78 μg/mL = 1.53 μM; T_max = 1.0 h; AUC_last = 2.06 μg · h/mL; 84 mg/kg, p.o.) and shown to display in vivo anti-inflammatory efficacy against LPS-induced plasma IL-1β production (ED_max = 100 mg/kg, p.o.), Oxazolone-induced delayed-type hypersensitivity (ED_max = 50 mg/kg, p.o.), collagen-induced arthritis (ED_max = 100 mg/kg, p.o.). When administered via intraperitoneal injection, VX-765 is also demonstrated to suppress the severity of seizure induction (ED_max = 50 mg/kg i.p.) among rats receiving kainic acid via intracerebroventricular injection.

Cell permeable: yes

Caspase-1

Store at -20°C

[1] WOODS WANNAMAKER. (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]. Journal of Pharmacology and Experimental Therapeutics, 2007, 321 2: 509-516. DOI:10.1124/jpet.106.111344
[2] YI ZHANG. NLRP3 Inflammasome Mediates Chronic Mild Stress-Induced Depression in Mice via Neuroinflammation.[J]. International Journal of Neuropsychopharmacology, 2015, 18 8. DOI:10.1093/ijnp/pyv006
[3] BRIENNE A MCKENZIE. Caspase-1 inhibition prevents glial inflammasome activation and pyroptosis in models of multiple sclerosis.[J]. Proceedings of the National Academy of Sciences of the United States of America, 2018: E6065-E6074. DOI:10.1073/pnas.1722041115
[4] YIYI LI . VX-765 attenuates atherosclerosis in ApoE deficient mice by modulating VSMCs pyroptosis[J]. Experimental cell research, 2020, 389 1: Article 111847. DOI:10.1016/j.yexcr.2020.111847
[5] MATTIA MAROSO . Interleukin-1β Biosynthesis Inhibition Reduces Acute Seizures and Drug Resistant Chronic Epileptic Activity in Mice[J]. Neurotherapeutics, 2011, 8 2: Pages 304-315. DOI:10.1007/s13311-011-0039-z
[6] F.M. NOE . Pharmacological blockade of IL-1β/IL-1 receptor type 1 axis during epileptogenesis provides neuroprotection in two rat models of temporal lobe epilepsy[J]. Neurobiology of Disease, 2013, 59: Pages 183-193. DOI:10.1016/j.nbd.2013.07.015
[7] QIAN LI . Caspase-1 inhibition mediates neuroprotection in experimental stroke by polarizing M2 microglia/macrophage and suppressing NF-κB activation[J]. Biochemical and biophysical research communications, 2019, 513 2: Pages 479-485. DOI:10.1016/j.bbrc.2019.03.202
[8] JOSEPH FLORES. Caspase-1 inhibition alleviates cognitive impairment and neuropathology in an Alzheimer’s disease mouse model.[J]. Nature Communications, 2018: 3916. DOI:10.1038/s41467-018-06449-x