VRT-043198
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MedKoo CAT#: 205941

CAS#: 244133-31-1

Description: VRT-043198, the active metabolite of VX-765 (Belnacasan), 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 it had little effect on the release of several other cytokines, including IL-1alpha, tumor necrosis factor-alpha, IL-6 and IL-8.


Chemical Structure

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VRT-043198
CAS# 244133-31-1

Theoretical Analysis

MedKoo Cat#: 205941
Name: VRT-043198
CAS#: 244133-31-1
Chemical Formula: C22H29ClN4O6
Exact Mass: 480.17756
Molecular Weight: 480.94
Elemental Analysis: C, 54.94; H, 6.08; Cl, 7.37; N, 11.65; O, 19.96

Price and Availability

Size Price Availability Quantity
5.0mg USD 150.0 Ready to ship
10.0mg USD 250.0 Ready to ship
25.0mg USD 450.0 Ready to ship
50.0mg USD 750.0 Ready to ship
100.0mg USD 1250.0 Ready to ship
200.0mg USD 1950.0 Ready to ship
500.0mg USD 3650.0 Ready to ship
1.0g USD 5850.0 Ready to ship
2.0g USD 9950.0 Ready to ship
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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: 1. 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) 2. 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

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 50.0 103.96

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.

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. 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.

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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.

1: 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. PubMed PMID: 28837200.

2: 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-butanoy l)-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. Epub 2007 Feb 8. PubMed PMID: 17289835.