Belnacasan (VX765)
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MedKoo CAT#: 203165

CAS#: 273404-37-8

Description: 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

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Belnacasan (VX765)
CAS# 273404-37-8

Theoretical Analysis

MedKoo Cat#: 203165
Name: Belnacasan (VX765)
CAS#: 273404-37-8
Chemical Formula: C24H33ClN4O6
Exact Mass: 508.20886
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 Quantity
10.0mg USD 70.0 Ready to ship
25.0mg USD 150.0 Ready to ship
50.0mg USD 250.0 Ready to ship
100.0mg USD 450.0 Ready to ship
200.0mg USD 750.0 Ready to ship
500.0mg USD 1650.0 Ready to ship
1.0g USD 2950.0 Ready to ship
2.0g USD 5250.0 Ready to ship
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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 – 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

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/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 57.73 113.41
DMF 30.0 58.94
Ethanol 60.3 118.47
Ethanol:PBS (pH 7.2) (1:9) 0.1 0.2
Water 1.0 1.96

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.

Recalculate based on batch purity %
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: 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.
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.

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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

 1: Noe FM, Polascheck N, Frigerio F, Bankstahl M, Ravizza T, Marchini S, Beltrame L, Banderó CR, Löscher W, Vezzani A. Pharmacological blockade of IL-1β/IL-1 receptor type 1 axis during epileptogenesis provides neuroprotection in two rat models of temporal lobe epilepsy. Neurobiol Dis. 2013 Nov;59:183-93. doi: 10.1016/j.nbd.2013.07.015. Epub 2013 Aug 9. PubMed PMID: 23938763.

2: Bialer M, Johannessen SI, Levy RH, Perucca E, Tomson T, White HS. Progress report on new antiepileptic drugs: a summary of the Eleventh Eilat Conference (EILAT XI). Epilepsy Res. 2013 Jan;103(1):2-30. doi: 10.1016/j.eplepsyres.2012.10.001. Epub 2012 Dec 4. Review. PubMed PMID: 23219031.

3: Boxer MB, Shen M, Auld DS, Wells JA, Thomas CJ. A small molecule inhibitor of Caspase 1. 2010 Feb 25 [updated 2011 Mar 3]. Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010-. Available from http://www.ncbi.nlm.nih.gov/books/NBK56241/ PubMed PMID: 21735610.

4: Akin D, Ravizza T, Maroso M, Carcak N, Eryigit T, Vanzulli I, Aker RG, Vezzani A, Onat FY. IL-1β is induced in reactive astrocytes in the somatosensory cortex of rats with genetic absence epilepsy at the onset of spike-and-wave discharges, and contributes to their occurrence. Neurobiol Dis. 2011 Dec;44(3):259-69. doi: 10.1016/j.nbd.2011.05.015. Epub 2011 May 30. PubMed PMID: 21645619.

5: Maroso M, Balosso S, Ravizza T, Iori V, Wright CI, French J, Vezzani A. Interleukin-1β biosynthesis inhibition reduces acute seizures and drug resistant chronic epileptic activity in mice. Neurotherapeutics. 2011 Apr;8(2):304-15. doi: 10.1007/s13311-011-0039-z. PubMed PMID: 21431948; PubMed Central PMCID: PMC3101825.

6: Yu JR, Leslie KS. Cryopyrin-associated periodic syndrome: an update on diagnosis and treatment response. Curr Allergy Asthma Rep. 2011 Feb;11(1):12-20. doi: 10.1007/s11882-010-0160-9. PubMed PMID: 21104172; PubMed Central PMCID: PMC3020304.

7: Boxer MB, Quinn AM, Shen M, Jadhav A, Leister W, Simeonov A, Auld DS, Thomas CJ. A highly potent and selective caspase 1 inhibitor that utilizes a key 3-cyanopropanoic acid moiety. ChemMedChem. 2010 May 3;5(5):730-8. doi: 10.1002/cmdc.200900531. PubMed PMID: 20229566; PubMed Central PMCID: PMC3062473.

8: Ravizza T, Noé F, Zardoni D, Vaghi V, Sifringer M, Vezzani A. Interleukin Converting Enzyme inhibition impairs kindling epileptogenesis in rats by blocking astrocytic IL-1beta production. Neurobiol Dis. 2008 Sep;31(3):327-33. doi: 10.1016/j.nbd.2008.05.007. Epub 2008 May 29. PubMed PMID: 18632279.

9: Tanoury GJ, Chen M, Dong Y, Forslund RE, Magdziak D. Development of a novel Pd-catalyzed N-acyl vinylogous carbamate synthesis for the key intermediate of ICE inhibitor VX-765. Org Lett. 2008 Jan 17;10(2):185-8. Epub 2007 Dec 15. PubMed PMID: 18081302.

10: Cornelis S, Kersse K, Festjens N, Lamkanfi M, Vandenabeele P. Inflammatory caspases: targets for novel therapies. Curr Pharm Des. 2007;13(4):367-85. Review. PubMed PMID: 17311555



Additional Information

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.