Synonym
VRT043198, VRT-043198, VRT 043198; mitabolite of VX-765 (Belnacasan);
IUPAC/Chemical Name
1. (2S)-1-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanoyl)-N-((3S)-2-hydroxy-5-oxotetrahydrofuran-3-yl)pyrrolidine-2-carboxamide (ring-close)
2. (S)-3-((S)-1-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanoyl)pyrrolidine-2-carboxamido)-4-oxobutanoic acid (ring open)
InChi Key
GGAMPJOZFRKVQR-CIWGKMQQSA-N; SOZONDBMOYWSRW-QANKJYHBSA-N.
InChi Code
InChI=1S/C22H29ClN4O6/c1-22(2,3)17(26-18(29)11-6-7-13(24)12(23)9-11)20(31)27-8-4-5-15(27)19(30)25-14-10-16(28)33-21(14)32/h6-7,9,14-15,17,21,32H,4-5,8,10,24H2,1-3H3,(H,25,30)(H,26,29)/t14-,15-,17+,21?/m0/s1;
InChI=1S/C22H29ClN4O6/c1-22(2,3)18(26-19(31)12-6-7-15(24)14(23)9-12)21(33)27-8-4-5-16(27)20(32)25-13(11-28)10-17(29)30/h6-7,9,11,13,16,18H,4-5,8,10,24H2,1-3H3,(H,25,32)(H,26,31)(H,29,30)/t13-,16-,18+/m0/s1
SMILES Code
O=C([C@H]1N(C([C@H](C(C)(C)C)NC(C2=CC=C(N)C(Cl)=C2)=O)=O)CCC1)N[C@@H](C3)C(O)OC3=O (ring-close); 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](CC(O)=O)C=O (ring-open)
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
Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility
Soluble in DMSO, not in water
Shelf Life
>5 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:
VRT-043198 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:
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 it 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 it did not affect the proliferation of activated primary T cells or T-cell lines.
Reference: J Pharmacol Exp Ther. 2007 May;321(2):509-16. https://jpet.aspetjournals.org/content/321/2/509.long
In vivo activity:
VX-765 was efficiently converted to VRT-043198 when administered orally to mice, and it inhibited lipopolysaccharide-induced cytokine secretion. In addition, VX-765 reduced disease severity and the expression of inflammatory mediators in models of rheumatoid arthritis and skin inflammation. These data suggest that VX-765 is a novel cytokine inhibitor useful for treatment of inflammatory diseases.
Reference: J Pharmacol Exp Ther. 2007 May;321(2):509-16. https://jpet.aspetjournals.org/content/321/2/509.long
|
Solvent |
mg/mL |
mM |
| Solubility |
| DMSO |
50.0 |
103.96 |
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
480.94
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. Wannamaker W, Davies R, Namchuk M, Pollard J, Ford P, Ku G, Decker C, Charifson P, Weber P, Germann UA, Kuida K, Randle JC. (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. doi: 10.1124/jpet.106.111344. Epub 2007 Feb 8. PMID: 17289835.
In vitro protocol:
1. Wannamaker W, Davies R, Namchuk M, Pollard J, Ford P, Ku G, Decker C, Charifson P, Weber P, Germann UA, Kuida K, Randle JC. (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. doi: 10.1124/jpet.106.111344. Epub 2007 Feb 8. PMID: 17289835.
In vivo protocol:
1. Wannamaker W, Davies R, Namchuk M, Pollard J, Ford P, Ku G, Decker C, Charifson P, Weber P, Germann UA, Kuida K, Randle JC. (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. doi: 10.1124/jpet.106.111344. Epub 2007 Feb 8. PMID: 17289835.
1: Lloyd JR, Biasutto A, Dürr KL, Jazayeri A, Hopper JTS, Oldham NJ. Mapping the Binding Interactions between Human Gasdermin D and Human Caspase-1 Using Carbene Footprinting. JACS Au. 2023 Jun 23;3(7):2025-2035. doi: 10.1021/jacsau.3c00236. PMID: 37502151; PMCID: PMC10369405.
2: Yang XM, Cohen MV, Sayner S, Audia JP, Downey JM. Lethal Caspase-1/4-Dependent Injury Occurs in the First Minutes of Coronary Reperfusion and Requires Calpain Activity. Int J Mol Sci. 2023 Feb 14;24(4):3801. doi: 10.3390/ijms24043801. PMID: 36835212; PMCID: PMC9960231.
3: Tang Q, Guo Q, Li K, Fei F. VRT-043198 Ameliorates Surgery-Induced Neurocognitive Disorders by Restoring the NGF and BNDF Expression in Aged Mice. Neuropsychiatr Dis Treat. 2022 May 16;18:1027-1037. doi: 10.2147/NDT.S364250. PMID: 35607505; PMCID: PMC9123246.
4: Zou C, Beard JA, Yang G, Evans WE, Bonten EJ. CASPorter: A Novel Inducible Human CASP1/NALP3/ASC Inflammasome Biosensor. J Inflamm Res. 2022 Feb 19;15:1183-1194. doi: 10.2147/JIR.S333725. PMID: 35221708; PMCID: PMC8865862.
5: 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.
6: Audia JP, Yang XM, Crockett ES, Housley N, Haq EU, O'Donnell K, Cohen MV, Downey JM, Alvarez DF. Caspase-1 inhibition by VX-765 administered at reperfusion in P2Y12 receptor antagonist-treated rats provides long- term reduction in myocardial infarct size and preservation of ventricular function. Basic Res Cardiol. 2018 Jul 10;113(5):32. doi: 10.1007/s00395-018-0692-z. PMID: 29992382; PMCID: PMC6396295.
7: Adriaenssens Y, Jiménez Fernández D, Vande Walle L, Elvas F, Joossens J, Lambeir A, Augustyns K, Lamkanfi M, Van der Veken P. Carboxylate isosteres for caspase inhibitors: the acylsulfonamide case revisited. Org Biomol Chem. 2017 Sep 13;15(35):7456-7473. doi: 10.1039/c7ob01403a. PMID: 28837200.
8: Wannamaker W, Davies R, Namchuk M, Pollard J, Ford P, Ku G, Decker C, Charifson P, Weber P, Germann UA, Kuida K, Randle JC. (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. doi: 10.1124/jpet.106.111344. Epub 2007 Feb 8. PMID: 17289835.
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. Carmo HRP, Castillo AR, Bonilha I, Gomes EIL, Barreto J, Moura FA, Davanzo GG, de Brito Monteiro L, Muraro SP, Fabiano de Souza G, Morari J, Galdino FE, Brunetti NS, Reis-de-Oliveira G, Carregari VC, Nadruz W, Martins-de-Souza D, Farias AS, Velloso LA, Proenca-Modena JL, Mori MA, Loh W, Bhatt DL, Yellon DM, Davidson SM, De Oliveira PG, Moraes-Vieira PM, Sposito AC. Diacerein reduces inflammasome activation and SARS-CoV-2 virus replication: a proof-of-concept translational study. Front Pharmacol. 2024 Oct 7;15:1402032. doi: 10.3389/fphar.2024.1402032. PMID: 39434905; PMCID: PMC11491754.
