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Vanin-1-IN-1 is a novel and potent inhibitor of vanin-1 enzyme, a cell surface associated, giycosyiphosphatidyS inositol (GPi) anchored protein which plays an important role in metabolism and inflammation.
| Targets |
Vanin-1-IN-1 targets Vanin-1 enzyme with an IC50 of 2.3 nM (recombinant human Vanin-1) [1]
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| ln Vitro |
Vanin-1-IN-1 (0.1 nM–50 nM) dose-dependently inhibited recombinant human Vanin-1 enzyme activity: 1 nM achieved 48% inhibition, 10 nM achieved 92% inhibition, and 50 nM maintained >95% inhibition [1]
In human hepatocyte-like cells (HepG2) expressing Vanin-1, Vanin-1-IN-1 (1 nM–20 nM) dose-dependently reduced pantetheinase activity (Vanin-1 catalytic activity): 10 nM reduced pantetheinase activity by 76% compared to the control group [1] Vanin-1-IN-1 showed high selectivity for Vanin-1 over related enzymes (Vanin-2, Vanin-3): IC50 > 1000 nM for both Vanin-2 and Vanin-3 [1] At concentrations up to 100 nM, Vanin-1-IN-1 did not affect HepG2 cell viability (viability > 90%) as assessed by MTT assay [1] |
| Enzyme Assay |
Vanin-1 enzyme activity assay: Recombinant human Vanin-1 enzyme was incubated with Vanin-1-IN-1 (0.01 nM–1000 nM) in assay buffer containing pantetheine (substrate) and a colorimetric detection reagent. The reaction was carried out at 37°C for 60 minutes, and the absorbance of the reaction product (cysteamine-derived chromophore) was measured at 405 nm. Inhibition rates were calculated relative to the control group, and IC50 was obtained by fitting dose-response curves [1]
Selectivity assay: The same enzyme activity assay protocol was used for recombinant human Vanin-2 and Vanin-3 enzymes, with Vanin-1-IN-1 concentrations up to 1000 nM to evaluate off-target inhibition [1] |
| Cell Assay |
Cellular Vanin-1 pantetheinase activity assay: HepG2 cells were seeded in 96-well plates (1 × 10⁴ cells/well) and cultured for 24 hours. Cells were treated with Vanin-1-IN-1 (1 nM–20 nM) for 4 hours, then incubated with pantetheine substrate and detection reagent at 37°C for 30 minutes. Absorbance at 405 nm was measured to quantify pantetheinase activity, and inhibition rates were calculated [1]
Cell viability assay: HepG2 cells were seeded in 96-well plates (5 × 10³ cells/well) and treated with Vanin-1-IN-1 (0.1 nM–100 nM) for 72 hours. MTT reagent was added, and the plates were incubated for another 4 hours. Absorbance at 570 nm was measured to assess cell viability [1] |
| Animal Protocol |
Acute inflammation mouse model: 6–8 week-old C57BL/6 mice were intraperitoneally injected with lipopolysaccharide (LPS) to induce acute inflammation. One hour prior to LPS injection, mice were randomized into vehicle and Vanin-1-IN-1 treatment groups (5 mg/kg, 10 mg/kg, p.o., n=8/group). Vanin-1-IN-1 was dissolved in 0.5% hydroxypropyl methylcellulose (HPMC) solution. Mice were sacrificed 6 hours post-LPS injection, and liver tissues were collected to measure Vanin-1 enzyme activity and pro-inflammatory cytokine (TNFα, IL-6) levels [1]
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| ADME/Pharmacokinetics |
In Sprague-Dawley rats, the bioavailability (F) of oral Vanin-1-IN-1 (20 mg/kg) was 51%, the peak plasma concentration (Cmax) was 980 ng/mL, the time to peak concentration (Tmax) was 1.3 h, and the elimination half-life (t1/2) was 7.2 h [1]. In C57BL/6 mice, the Cmax of oral Vanin-1-IN-1 (10 mg/kg) was 650 ng/mL, the Tmax was 1.0 h, and the volume of distribution (Vd) was 285 mL/kg [1]. Vanin-1-IN-1 showed good stability in human liver microsomes (t1/2 = 8.7 h) and mouse liver microsomes (t1/2 = 7.9 h) [1].
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| Toxicity/Toxicokinetics |
Acute toxicity studies in ICR mice: Oral administration of Vanin-1-IN-1 at doses up to 300 mg/kg did not cause death or significant toxic symptoms (weight loss, diarrhea, behavioral abnormalities) within 14 days [1]. Subchronic toxicity studies in Sprague-Dawley rats (oral administration of 10 mg/kg, 30 mg/kg, and 100 mg/kg daily for 28 days): No significant changes were observed in body weight, hematological parameters (white blood cells, red blood cells, platelets), or biochemical parameters (ALT, AST, BUN, creatinine). Histopathological examination of the liver, kidneys, heart, and lungs revealed no drug-related lesions [1].
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| References | |
| Additional Infomation |
Vanin-1-IN-1 is a novel small-molecule Vanin-1 enzyme inhibitor belonging to the pyrimidine carboxamide class of compounds [1]. Its mechanism of action involves selectively inhibiting the activity of Vanin-1 pantothenic acid thioacetylaminease, thereby reducing the production of cysteine (a pro-inflammatory mediator) and the subsequent release of pro-inflammatory cytokines [1]. This compound is being developed for the treatment of Vanin-1-mediated inflammatory diseases, including acute inflammation, liver inflammation, and autoimmune diseases [1]. Vanin-1-IN-1 exhibits good oral bioavailability, metabolic stability, and low toxicity, supporting its potential clinical application [1].
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| Molecular Formula |
C18H22N6O2
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|---|---|
| Molecular Weight |
354.406282901764
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| Exact Mass |
354.18
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| Elemental Analysis |
C, 61.00 H, 6.26 N, 23.71 O, 9.03
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| CAS # |
2173134-00-2
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| PubChem CID |
134177597
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| Appearance |
White to off-white solid powder
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| LogP |
0
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
26
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| Complexity |
476
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
VGRLXWFIXGZRMS-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C18H22N6O2/c25-16(24-6-1-18(13-24)2-7-26-8-3-18)14-9-21-17(22-10-14)23-12-15-11-19-4-5-20-15/h4-5,9-11H,1-3,6-8,12-13H2,(H,21,22,23)
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| Chemical Name |
(2-((pyrazin-2-ylmethyl)amino)pyrimidin-5-yl)(8-oxa-2-azaspiro[4.5]decan-2-yl)methanone
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| Synonyms |
Vanin-1-IN-1 Vanin-1IN-1 Vanin-1 IN-1
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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 : ~125 mg/mL (~352.70 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (5.87 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 20.8 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: ≥ 2.08 mg/mL (5.87 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 20.8 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: ≥ 2.08 mg/mL (5.87 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 | 2.8216 mL | 14.1080 mL | 28.2159 mL | |
| 5 mM | 0.5643 mL | 2.8216 mL | 5.6432 mL | |
| 10 mM | 0.2822 mL | 1.4108 mL | 2.8216 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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