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VRT-043198 is a metabolite of Belnacasan (VX-765), which is a BBB-permeable inhibitor of interleukin-converting enzyme/caspase-1 subfamily caspases. VRT-043198 inhibits ICE/caspase-1 and caspase-4 with Ki values of 0.8 nM and 0.6 nM, respectively.
| Targets |
Interleukin-converting enzyme/caspase-1 subfamily caspases; Caspase-4 (Kd < 0.6 nM); Caspase-1 (Ki = 0.8 nM); active metabolite of VX-765 (Belnacasan)
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|---|---|
| ln Vitro |
VRT-043198 exhibits selectivity for other caspases-3 and -6 to -9 that is 100–10,000 times more [1]. While VRT043198 has no influence on the release of various other cytokines, such as IL-1α, tumor necrosis factor, IL-6, and IL-8, it suppresses the release of interleukin (IL)-1β and IL-18. In PBMC (n = 8) and whole blood (n = 4), VRT-043198 suppresses the release of IL-1β with IC50 values of 0.67±0.55 and 1.9±0.80 nM, respectively [1]. Strong anti-apoptotic activity is absent in VRT-043198 [1].
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| ln Vivo |
Hepatic and plasma esterases convert VX-765 to VRT-043198 very quickly, but aqueous solutions convert it considerably more slowly [1]. In models of rheumatoid arthritis and skin inflammation, VX765 lessens the severity of the disease and the expression of inflammatory mediators [1]. The release of cytokines generated by lipopolysaccharide is inhibited by VX765 (25, 50, 100, or 200 mg/kg) [1].
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| Enzyme Assay |
As is a Caspase inhibitor, VRT-043198 exhibits 100- to 10,000-fold selectivity against other caspase-3 and -6 to -9. 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.
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| Animal Protocol |
Animal/Disease Models: naive male CD-1 mice [1].
Doses: 25-200 mg/kg. Route of Administration: po (oral gavage) 1 hour before intravenous (iv) (iv)injection of 2 mg/kg E. coli LPS (strain 0111:B4). Experimental Results: Serum IL-1β levels were diminished. |
| References | |
| Additional Infomation |
(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) is an orally absorbed prodrug of (S)-3-({1-[(S)-1-((S)-2-{[1-(4-amino-3-chlorophenyl)-methanoyl]-amino}-3,3-dimethyl-butanoyl)-pyrrolidin-2yl]-methanoyl}-amino)-4-oxo-butyric acid (VRT-043198), a potent and selective inhibitor of interleukin-converting enzyme/caspase-1 subfamily caspases. VRT-043198 exhibits 100- to 10,000-fold selectivity against other caspase-3 and -6 to -9. The therapeutic potential of VX-765 was assessed by determining the effects of VRT-043198 on cytokine release by monocytes in vitro and of orally administered VX-765 in several animal models in vivo. 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. 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.[1]
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| Molecular Formula |
C22H29CLN4O6
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|---|---|
| Molecular Weight |
480.941864728928
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| Exact Mass |
480.178
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| Elemental Analysis |
C, 54.94; H, 6.08; Cl, 7.37; N, 11.65; O, 19.96
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| CAS # |
244133-31-1
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| PubChem CID |
11443029
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| Appearance |
White to off-white solid powder
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| LogP |
2.517
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
9
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| Heavy Atom Count |
33
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| Complexity |
771
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| Defined Atom Stereocenter Count |
3
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| SMILES |
ClC1=C(C=CC(=C1)C(N[C@H](C(N1CCC[C@H]1C(N[C@H](C=O)CC(=O)O)=O)=O)C(C)(C)C)=O)N
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| InChi Key |
SOZONDBMOYWSRW-QANKJYHBSA-N
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| InChi Code |
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
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| Chemical Name |
(3S)-3-[[(2S)-1-[(2S)-2-[(4-amino-3-chlorobenzoyl)amino]-3,3-dimethylbutanoyl]pyrrolidine-2-carbonyl]amino]-4-oxobutanoic acid
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| Synonyms |
VRT-043198; 244133-31-1; UNII-Q257O24H4J; VRT 043198; Q257O24H4J; VRT043198; L-Prolinamide, N-(4-amino-3-chlorobenzoyl)-3-methyl-L-valyl-N-((1S)-2-carboxy-1-formylethyl)-; (3S)-3-[[(2S)-1-[(2S)-2-[(4-amino-3-chlorobenzoyl)amino]-3,3-dimethylbutanoyl]pyrrolidine-2-carbonyl]amino]-4-oxobutanoic acid;
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~180 mg/mL (~374.27 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: 4.5 mg/mL (9.36 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 45.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 4.5 mg/mL (9.36 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 45.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 4.5 mg/mL (9.36 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0793 mL | 10.3963 mL | 20.7926 mL | |
| 5 mM | 0.4159 mL | 2.0793 mL | 4.1585 mL | |
| 10 mM | 0.2079 mL | 1.0396 mL | 2.0793 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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