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Purity: ≥98%
ML132 (also known as NCGC 00185682) is a potent and selective caspase 1 inhibitor with an IC50 of 0.316 nM. It contains a nitrile-containing propionic acid moiety as an electrophile for covalent attack by the active-site cysteine residue of caspase 1. The syntheses of several cyanopropanate-containing small molecules based on the optimized peptidic scaffold of prodrug VX-765 were accomplished. These compounds were found to be potent inhibitors of caspase 1 (IC(50) values < or =1 nM). Examination of these novel small molecules against a caspase panel demonstrated an impressive degree of selectivity for caspase 1 inhibition over other caspase isozymes. Assessment of hydrolytic stability and selected ADME properties highlighted these agents as potentially useful tools for studying caspase 1 down-regulation in various settings, including in vivo analyses.
| Targets |
Caspase 1
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| ln Vitro |
Researchers examined VRT-043198 (2b), ML132 (NCGC 00185682) (3), NCGC00183434 (4) and the tetrazole NCGC00183681 (16) and the results are displayed in figure 2. VRT-043198 (2b) was confirmed as a potent caspase 1 inhibitor with an IC50 value of 11.5 nM. NCGC00183434 (4) which contains the key cyanopropanoate moiety was found to inhibit caspase 1 with an impressive IC50 value of 0.316 nM. We were further gratified to find that the ethyl ester 3 and tetrazole 16 retained impressive potencies versus caspase 1 (IC50 = 144.7 nM and IC50 = 20.4 nM, respectively). The KI value of 4 was estimated to be 0.4 nM for caspase 1 using a competitive inhibition model [1].
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| ADME/Pharmacokinetics |
Based on our data, these compounds are clearly important new tools for inhibiting caspase 1. However, the functional groups of these compounds (e.g., acetals, aldehydes, nitriles, and esters) are susceptible to hydrolysis under various conditions. Therefore, a thorough understanding of their stability is crucial for assessing their applicability as molecular probes and even clinical drugs. To this end, we conducted aqueous degradation studies on compounds 1, 2b, 3/ML132 (NCGC 00185682), 4, and 16 under neutral (pH 7), acidic (pH 2), and alkaline (pH 8) conditions. The study used liquid chromatography-mass spectrometry (LCMS) to monitor the degradation of each compound at different time points over 96 hours (Figure 3). Prodrug 1 showed moderate degradation in water, with over 50% of the compound decomposing after 48 hours. This degradation was exacerbated under both acidic and alkaline conditions. Conversely, active ingredient 2b was very stable under both neutral and acidic conditions, with moderate degradation at pH 8. The potent compound 4 was extremely stable under alkaline conditions and moderate to good stability under neutral and acidic conditions (50% degradation after 72 hours under both conditions). Ethyl ester 3/ML132 (NCGC 00185682) was unusually stable under neutral and acidic conditions (no degradation observed), but completely degraded after 22 hours under alkaline conditions (presumably due to saponification of the ester). Finally, tetrazolium 16 showed resistance to degradation under all conditions. It is noteworthy that these data suggest that compound 1 may have a short half-life as an oral medication because it is unstable under acidic conditions (e.g., the gastric environment) (40% degradation after 3.5 hours at pH 2). In contrast, these data strongly suggest that 3/ML132 (NCGC 00185682) and 16 would be suitable reagents for various tests (based on cellular and in vivo studies), and even the highly active 4 could persist for more than 24 hours. [1]
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| References | |
| Additional Infomation |
(3S)-3-[[[(2S)-1-[(2S)-2-[[(4-amino-3-chlorophenyl)-oxymethyl]amino]-3,3-dimethyl-1-oxybutyl]-2-pyrrolidinyl]-oxymethyl]amino]-3-cyanopropionic acid is a peptide. This paper investigates the potential of the nitrile-containing propionic acid moiety as an electrophilic agent to covalently attack the cysteine residues at the active site of caspase 1. Based on an optimized peptide backbone of the prodrug VX-765, we synthesized several small molecules containing cyanopropionic acid esters. These compounds were found to be potent inhibitors of caspase 1 (IC50 ≤ 1 nM). Caspase activity assays of these novel small molecules showed that their inhibitory effect on caspase 1 was significantly superior to other caspase isoenzymes. Evaluation of hydrolytic stability and selected ADME properties suggests that these agents are potentially useful tools for studying caspase 1 downregulation under various conditions, including in vivo assays. [1]
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| Molecular Formula |
C22H28CLN5O5
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| Molecular Weight |
477.941224098206
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| Exact Mass |
477.177
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| Elemental Analysis |
C, 55.29; H, 5.90; Cl, 7.42; N, 14.65; O, 16.74
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| CAS # |
1230628-71-3
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| Related CAS # |
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| PubChem CID |
44620939
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| Appearance |
White to light yellow solid powder
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| LogP |
1.6
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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 |
8
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| Heavy Atom Count |
33
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| Complexity |
820
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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(NC[C@@H](C#N)C(=O)O)=O)=O)C(C)(C)C)=O)N
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| InChi Key |
KENKPOUHXLJLEY-QANKJYHBSA-N
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| InChi Code |
InChI=1S/C22H28ClN5O5/c1-22(2,3)18(27-19(31)12-6-7-15(25)14(23)9-12)21(33)28-8-4-5-16(28)20(32)26-13(11-24)10-17(29)30/h6-7,9,13,16,18H,4-5,8,10,25H2,1-3H3,(H,26,32)(H,27,31)(H,29,30)/t13-,16-,18+/m0/s1
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| Chemical Name |
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| Synonyms |
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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 Note: (1). This product requires protection from light (avoid light exposure) during transportation and storage. (2). Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture. |
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| 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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 7 mg/mL (14.65 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 70.0 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. Solubility in Formulation 2: ≥ 6.25 mg/mL (13.08 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% 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 62.5 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. View More
Solubility in Formulation 3: ≥ 6.25 mg/mL (13.08 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 | 2.0923 mL | 10.4616 mL | 20.9231 mL | |
| 5 mM | 0.4185 mL | 2.0923 mL | 4.1846 mL | |
| 10 mM | 0.2092 mL | 1.0462 mL | 2.0923 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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Complete response curves for VRT-043198 (2b) ( |
Aqueous stability of prodrugs VX-765 (1)(◆) and NCGC00185682 (3)(X) and drugs VRT-043198 (2b)(▲), NCGC00183434 (4)(■) and NCGC00183681 (16)(●) at neutral (pH 7 - black), acidic (pH 2 - red), and basic (pH 8 - blue) conditions. |
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COA
IC50= 11.5 nM), NCGC00185682 (3) (
IC50= 144.7 nM), NCGC00183434 (4) (◆ IC50= 0.316 nM)and the tetrazole NCGC00183681 (16) (■ IC50= 20.4 nM).