Belnacasan | VX-765 | CAS# 273404-37-8 | Caspase Inhibitor

MedKoo Cat#: 203165 | Name: Belnacasan (VX765)

Description:

WARNING: This product is for research use only, not for human or veterinary use.

Belnacasan, also known as VX-765, is designed to inhibit Caspase, which is an enzyme that controls the generation of two cytokines, IL-1b and IL-18. VX-765 has been shown to inhibit acute seizures in preclinical models. In addition, VX-765 has shown activity in preclinical models of chronic epilepsy. VX-765 had been dosed in over 100 patients in phase-I and phase-IIa clinical trials relating to other diseases, including a 28-day phase-IIa clinical trial in patients with psoriasis. It has completed the treatment phase of a phase-IIa clinical trial of VX-765 that enrolled approximately 75 patients with treatment-resistant epilepsy. The double-blind, randomized, placebo-controlled clinical trial was designed to evaluate the safety, tolerability and clinical activity of VX-765.

Chemical Structure

Belnacasan (VX765)

CAS#273404-37-8

Theoretical Analysis

MedKoo Cat#: 203165

Name: Belnacasan (VX765)

CAS#: 273404-37-8

Chemical Formula: C24H33ClN4O6

Exact Mass: 508.2089

Molecular Weight: 508.99

Elemental Analysis: C, 56.63; H, 6.53; Cl, 6.97; N, 11.01; O, 18.86

Price and Availability

Size	Price	Availability
5mg	USD 90.00	Ready to ship
10mg	USD 150.00	Ready to ship
25mg	USD 250.00	Ready to ship
50mg	USD 450.00	Ready to ship
100mg	USD 750.00	Ready to ship
200mg	USD 1,250.00	Ready to ship
500mg	USD 2,650.00	Ready to ship
1g	USD 4,250.00	Ready to ship

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Related CAS #

No Data

Synonym

VX 765, VX765, VX-765, Belnacasan

IUPAC/Chemical Name

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

InChi Key

SJDDOCKBXFJEJB-MOKWFATOSA-N

InChi Code

InChI=1S/C24H33ClN4O6/c1-5-34-23-16(12-18(30)35-23)27-21(32)17-7-6-10-29(17)22(33)19(24(2,3)4)28-20(31)13-8-9-15(26)14(25)11-13/h8-9,11,16-17,19,23H,5-7,10,12,26H2,1-4H3,(H,27,32)(H,28,31)/t16-,17-,19+,23+/m0/s1

SMILES Code

O=C([C@H]1N(C([C@@H](NC(C2=CC=C(N)C(Cl)=C2)=O)C(C)(C)C)=O)CCC1)N[C@@H](C3)[C@H](OCC)OC3=O

Appearance

White to off-white solid powder

Purity

>98% (or refer to the Certificate of Analysis)

Shipping Condition

Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition

0 Â– 4 o C for short term (weeks to 1 month) or -20 o C for long terms (months to years).

Solubility

soluble in DMSO, not soluble in water.

Shelf Life

>2 years if stored properly.

Drug Formulation

This drug may be formulated in DMSO

Stock Solution Storage

0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code

2934.99.9001

More Info

VX-765 is a novel Caspase-1 inhibitor being investigated for the treatment of epilepsy., currently being developed by Vertex. VX-765 is an orally-absorbed pro-drug of VRT-043198, a potent and selective inhibitor of ICE/caspase-1 sub-family caspases. VRT-043198 exhibits 100-10,000-fold selectivity against other caspase-3 and -6-9. In cultures of peripheral blood mononuclear cells and whole blood from healthy subjects stimulated with bacterial products, VRT-043198 inhibited the release of Interleukin (IL)-1beta and IL-18, but had little effect on the release of several other cytokines, including IL-1alpha, tumor necrosis factor-alpha, IL-6 and IL-8. In contrast, VRT-043198 had little or no demonstrable activity in cellular models of apoptosis and did not affect the proliferation of activated primary T-cells or T-cell lines. VX-765 was efficiently converted to VRT-043198 when administered orally to mice and inhibited LPS-induced cytokine secretion. In addition, VX-765 reduced disease severity and the expression of inflammatory mediators in models of rheumatoid arthritis and skin inflammation. According to Vertex's website, VX-765 has been shown to inhibit acute seizures in preclinical models of acute epilepsy and has shown activity in preclinical models of chronic epilepsy that do not respond to standard anti-epileptic drugs. Vertex recently initiated a Phase 2 proof-of-concept clinical trial of VX-765 in patients with epilepsy, which could result in interim clinical data being available as early as the second half of 2010. The Phase 2 trial for VX-765 is expected to enroll approximately 75 patients with treatment-resistant epilepsy.

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot#S21S03C04

QC Data

View QC data: current batch, Lot#S21S03C04

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

Biological target:

Belnacasan (VX-765) is the prodrug of VRT-043198, which is an inhibitor of IL-converting enzyme (ICE)/caspase-1 with Kis of 0.8 nM and less than 0.6 nM for caspase-1 and caspase-4, respectively.

In vitro activity:

Next, VX-765 was utilized to assess caspase-1 role in PX (paraoxon)-induced inflammatory response in the BBB. First, VX-765 inhibited the adhesion of PBMCs to BLECs monolayers (Fig. 4a). Second, VX-765 reversed the transmigration of PBMCs (peripheral blood mononuclear cells) across the BBB model back to control levels (Fig. 4b), and third, VX-765 attenuated the PX-induced increase in expression of the adhesion molecules ICAM-1 and E-selectin (Fig.4c, d, and e). The images shown in Fig. 4c represent the increase in ICAM-1 staining, and an increased localization of E-selectin in cell-cell junctions (arrows), and demonstrate that these effects are attenuated with the inhibition of caspase-1. These multifaceted effects demonstrate that caspase-1 has a key role in triggering the immune response in BLECs following PX exposure. Reference: J Neuroinflammation. 2020; 17: 267. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7488082/

In vivo activity:

Activated Casp1 cleaves the inflammatory cytokines IL-1β and IL-18 into their active states, leading to IL-1β-mediated inflammation through microglial activation and astrogliosis. IL-1β and IL-18 were assessed to determine whether Casp1 is directly implicated in inflammation in the J20 brain. There were no differences in hippocampal IL-1β and IL-18 mRNA levels between groups across any WO period, except for increased Il-1β mRNA in the J20 hippocampus that was normalized with VX-765 treatment at 16-week WO (Fig. 5a and Supplementary Fig. 6a). Pro-, active (Δ) and total (pro + active) IL-1β protein levels were measured by western blot in the hippocampus and cortex at 4- and 20-week WO (Fig. 5b). While hippocampal pro IL-1β levels remained unchanged (Fig. 5c, f), active and total IL-1β levels seemed higher in vehicle-treated J20 versus WT mice at both 4- and 20-week WO (Fig. 5d, e, g, h). This trend of increased active and total hippocampal IL-1β levels was not observed with VX-765 treatment. Active IL-1β levels were significantly higher in vehicle-treated J20 cortex but were normalized with VX-765 treatment at 20-week WO (Fig. 5g). Reference: Nat Commun. 2020; 11: 4571. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486940/

	Solvent	mg/mL	mM
Solubility
	DMSO	57.7	113.41
	DMF	30.0	58.94
	Ethanol	60.3	118.47
	Ethanol:PBS (pH 7.2) (1:9)	0.1	0.20
	Water	1.0	1.96

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 508.99 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Concentration / Solvent Volume / Mass	1 mg	5 mg	10 mg
1 mM	1.15 mL	5.76 mL	11.51 mL
5 mM	0.23 mL	1.15 mL	2.3 mL
10 mM	0.12 mL	0.58 mL	1.15 mL
50 mM	0.02 mL	0.12 mL	0.23 mL

Formulation protocol:

1. Israelov H, Ravid O, Atrakchi D, Rand D, Elhaik S, Bresler Y, Twitto-Greenberg R, Omesi L, Liraz-Zaltsman S, Gosselet F, Schnaider Beeri M, Cooper I. Caspase-1 has a critical role in blood-brain barrier injury and its inhibition contributes to multifaceted repair. J Neuroinflammation. 2020 Sep 9;17(1):267. doi: 10.1186/s12974-020-01927-w. PMID: 32907600; PMCID: PMC7488082. 2. Stack JH, Beaumont K, Larsen PD, Straley KS, Henkel GW, Randle JC, Hoffman HM. 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. doi: 10.4049/jimmunol.175.4.2630. PMID: 16081838. 3. Chen J, Chen YQ, Shi YJ, Ding SQ, Shen L, Wang R, Wang QY, Zha C, Ding H, Hu JG, Lü HZ. VX-765 reduces neuroinflammation after spinal cord injury in mice. Neural Regen Res. 2021 Sep;16(9):1836-1847. doi: 10.4103/1673-5374.306096. PMID: 33510091. 4. Flores J, Noël A, Foveau B, Beauchet O, LeBlanc AC. Pre-symptomatic Caspase-1 inhibitor delays cognitive decline in a mouse model of Alzheimer disease and aging. Nat Commun. 2020 Sep 11;11(1):4571. doi: 10.1038/s41467-020-18405-9. Erratum in: Nat Commun. 2021 Apr 9;12(1):2271. PMID: 32917871; PMCID: PMC7486940.

In vitro protocol:

In vivo protocol:

1. Chen J, Chen YQ, Shi YJ, Ding SQ, Shen L, Wang R, Wang QY, Zha C, Ding H, Hu JG, Lü HZ. VX-765 reduces neuroinflammation after spinal cord injury in mice. Neural Regen Res. 2021 Sep;16(9):1836-1847. doi: 10.4103/1673-5374.306096. PMID: 33510091. 2. Flores J, Noël A, Foveau B, Beauchet O, LeBlanc AC. Pre-symptomatic Caspase-1 inhibitor delays cognitive decline in a mouse model of Alzheimer disease and aging. Nat Commun. 2020 Sep 11;11(1):4571. doi: 10.1038/s41467-020-18405-9. Erratum in: Nat Commun. 2021 Apr 9;12(1):2271. PMID: 32917871; PMCID: PMC7486940.

1: Zahid A, Li B, Kombe AJK, Jin T, Tao J. Pharmacological Inhibitors of the NLRP3 Inflammasome. Front Immunol. 2019 Oct 25;10:2538. doi: 10.3389/fimmu.2019.02538. PMID: 31749805; PMCID: PMC6842943. 2: Tezcan G, Garanina EE, Alsaadi M, Gilazieva ZE, Martinova EV, Markelova MI, Arkhipova SS, Hamza S, McIntyre A, Rizvanov AA, Khaiboullina SF. Therapeutic Potential of Pharmacological Targeting NLRP3 Inflammasome Complex in Cancer. Front Immunol. 2021 Feb 3;11:607881. doi: 10.3389/fimmu.2020.607881. PMID: 33613529; PMCID: PMC7887322. 3: Li ZJ, Dai HQ, Huang XW, Feng J, Deng JH, Wang ZX, Yang XM, Liu YJ, Wu Y, Chen PH, Shi H, Wang JG, Zhou J, Lu GD. Artesunate synergizes with sorafenib to induce ferroptosis in hepatocellular carcinoma. Acta Pharmacol Sin. 2021 Feb;42(2):301-310. doi: 10.1038/s41401-020-0478-3. Epub 2020 Jul 22. PMID: 32699265; PMCID: PMC8026986. 4: Sun Z, Nyanzu M, Yang S, Zhu X, Wang K, Ru J, Yu E, Zhang H, Wang Z, Shen J, Zhuge Q, Huang L. VX765 Attenuates Pyroptosis and HMGB1/TLR4/NF-κB Pathways to Improve Functional Outcomes in TBI Mice. Oxid Med Cell Longev. 2020 Apr 15;2020:7879629. doi: 10.1155/2020/7879629. PMID: 32377306; PMCID: PMC7181015. 5: McKenzie BA, Mamik MK, Saito LB, Boghozian R, Monaco MC, Major EO, Lu JQ, Branton WG, Power C. Caspase-1 inhibition prevents glial inflammasome activation and pyroptosis in models of multiple sclerosis. Proc Natl Acad Sci U S A. 2018 Jun 26;115(26):E6065-E6074. doi: 10.1073/pnas.1722041115. Epub 2018 Jun 12. Erratum in: Proc Natl Acad Sci U S A. 2019 Jun 25;116(26):13145. PMID: 29895691; PMCID: PMC6042136. 6: Teng JF, Mei QB, Zhou XG, Tang Y, Xiong R, Qiu WQ, Pan R, Law BY, Wong VK, Yu CL, Long HA, Xiao XL, Zhang F, Wu JM, Qin DL, Wu AG. Polyphyllin VI Induces Caspase-1-Mediated Pyroptosis via the Induction of ROS/NF-κB/NLRP3/GSDMD Signal Axis in Non-Small Cell Lung Cancer. Cancers (Basel). 2020 Jan 13;12(1):193. doi: 10.3390/cancers12010193. PMID: 31941010; PMCID: PMC7017302. 7: Xu XE, Liu L, Wang YC, Wang CT, Zheng Q, Liu QX, Li ZF, Bai XJ, Liu XH. Caspase-1 inhibitor exerts brain-protective effects against sepsis-associated encephalopathy and cognitive impairments in a mouse model of sepsis. Brain Behav Immun. 2019 Aug;80:859-870. doi: 10.1016/j.bbi.2019.05.038. Epub 2019 May 27. PMID: 31145977. 8: Wang L, Dong X, Feng S, Pan H, Jang X, Chen L, Zhao Y, Chen W, Huang Z. VX765 alleviates dextran sulfate sodium-induced colitis in mice by suppressing caspase-1-mediated pyroptosis. Int Immunopharmacol. 2022 Jan;102:108405. doi: 10.1016/j.intimp.2021.108405. Epub 2021 Dec 2. PMID: 34865993. 9: Wen S, Deng F, Li L, Xu L, Li X, Fan Q. VX-765 ameliorates renal injury and fibrosis in diabetes by regulating caspase-1-mediated pyroptosis and inflammation. J Diabetes Investig. 2022 Jan;13(1):22-33. doi: 10.1111/jdi.13660. Epub 2021 Oct 12. PMID: 34494385; PMCID: PMC8756311. 10: Liu W, Shen J, Li Y, Wu J, Luo X, Yu Y, Zhang Y, Gu L, Zhang X, Jiang C, Li J. Pyroptosis inhibition improves the symptom of acute myocardial infarction. Cell Death Dis. 2021 Sep 16;12(10):852. doi: 10.1038/s41419-021-04143-3. PMID: 34531373; PMCID: PMC8445977. 11: Zhang Y, Zheng Y. Effects and mechanisms of potent caspase-1 inhibitor VX765 treatment on collagen-induced arthritis in mice. Clin Exp Rheumatol. 2016 Jan- Feb;34(1):111-8. Epub 2016 Jan 8. PMID: 26742834. 12: Su XL, Wang SH, Komal S, Cui LG, Ni RC, Zhang LR, Han SN. The caspase-1 inhibitor VX765 upregulates connexin 43 expression and improves cell-cell communication after myocardial infarction via suppressing the IL-1β/p38 MAPK pathway. Acta Pharmacol Sin. 2022 Sep;43(9):2289-2301. doi: 10.1038/s41401-021-00845-8. Epub 2022 Feb 7. PMID: 35132192; PMCID: PMC9433445. 13: Tian DD, Wang M, Liu A, Gao MR, Qiu C, Yu W, Wang WJ, Zhang K, Yang L, Jia YY, Yang CB, Wu YM. Antidepressant Effect of Paeoniflorin Is Through Inhibiting Pyroptosis CASP-11/GSDMD Pathway. Mol Neurobiol. 2021 Feb;58(2):761-776. doi: 10.1007/s12035-020-02144-5. Epub 2020 Oct 6. PMID: 33025508. 14: Li Y, Niu X, Xu H, Li Q, Meng L, He M, Zhang J, Zhang Z, Zhang Z. VX-765 attenuates atherosclerosis in ApoE deficient mice by modulating VSMCs pyroptosis. Exp Cell Res. 2020 Apr 1;389(1):111847. doi: 10.1016/j.yexcr.2020.111847. Epub 2020 Jan 20. PMID: 31972218. 15: Wu S, Li Z, Ye M, Liu C, Liu H, He X, Qin Y, Liang F, Pan L, Lin F. VX765, a Specific Caspase-1 Inhibitor, Alleviates Lung Ischemia Reperfusion Injury by Suppressing Endothelial Pyroptosis and Barrier Dysfunction. Biomed Res Int. 2021 Dec 22;2021:4525988. doi: 10.1155/2021/4525988. PMID: 34977239; PMCID: PMC8716216. 16: Zhang Z, Bai H, Ma X, Shen M, Li R, Qiu D, Li S, Gao L. Blockade of the NLRP3/caspase-1 axis attenuates ketamine-induced hippocampus pyroptosis and cognitive impairment in neonatal rats. J Neuroinflammation. 2021 Oct 19;18(1):239. doi: 10.1186/s12974-021-02295-9. PMID: 34666787; PMCID: PMC8527745. 17: Li H, Guo Z, Chen J, Du Z, Lu H, Wang Z, Xi J, Bai Y. Computational research of Belnacasan and new Caspase-1 inhibitor on cerebral ischemia reperfusion injury. Aging (Albany NY). 2022 Feb 22;14(4):1848-1864. doi: 10.18632/aging.203907. Epub 2022 Feb 22. PMID: 35193116; PMCID: PMC8908936. 18: Mula M. Emerging drugs for focal epilepsy. Expert Opin Emerg Drugs. 2013 Mar;18(1):87-95. doi: 10.1517/14728214.2013.750294. Epub 2012 Nov 26. PMID: 23176519. 19: Wang G, Zuo T, Li R. The mechanism of Arhalofenate in alleviating hyperuricemia-Activating PPARγ thereby reducing caspase-1 activity. Drug Dev Res. 2020 Nov;81(7):859-866. doi: 10.1002/ddr.21699. Epub 2020 Jun 7. PMID: 32506648. 20: Yang Z, Chen Z, Wang Y, Wang Z, Zhang D, Yue X, Zheng Y, Li L, Bian E, Zhao B. A Novel Defined Pyroptosis-Related Gene Signature for Predicting Prognosis and Treatment of Glioma. Front Oncol. 2022 Mar 31;12:717926. doi: 10.3389/fonc.2022.717926. PMID: 35433410; PMCID: PMC9008739.

1. Bassil F, Fernagut PO, Bezard E, Pruvost A, Leste-Lasserre T, Hoang QQ, Ringe D, Petsko GA, Meissner WG. Reducing C-terminal truncation mitigates synucleinopathy and neurodegeneration in a transgenic model of multiple system atrophy. Proc Natl Acad Sci U S A. 2016 Aug 23;113(34):9593-8. doi: 10.1073/pnas.1609291113. Epub 2016 Aug 1. PMID: 27482103; PMCID: PMC5003293. 2. Chen J, Chen YQ, Shi YJ, Ding SQ, Shen L, Wang R, Wang QY, Zha C, Ding H, Hu JG, Lü HZ. VX-765 reduces neuroinflammation after spinal cord injury in mice. Neural Regen Res. 2021 Sep;16(9):1836-1847. doi: 10.4103/1673-5374.306096. PMID: 33510091; PMCID: PMC8328782. 3. The contribution of interleukin-1 and retinoid acid receptor-related orphan receptor alpha to the pathogenesis of epidermolysis bullosa acquisita H Sadeghi - 2014 - zhb.uni-luebeck.de. link: https://www.zhb.uni-luebeck.de/epubs/ediss1543.pdf. 4. Lyu H, Ni H, Huang J, Yu G, Zhang Z, Zhang Q. VX-765 prevents intestinal ischemia-reperfusion injury by inhibiting NLRP3 inflammasome. Tissue Cell. 2021 Dec 24;75:101718. doi: 10.1016/j.tice.2021.101718. Epub ahead of print. PMID: 35131633.