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| Targets |
VIT-2763 specifically targets ferroportin (Fpn), a membrane protein responsible for the export of iron from cells into the blood. It acts as an inhibitor by directly binding to ferroportin. The compound has been shown to displace the peptide hormone hepcidin from its binding site on ferroportin with an IC50 of 24 nM.. By blocking the ferroportin-mediated iron export, VIT-2763 reduces the amount of iron released into the circulation, thereby limiting the availability of iron for erythropoiesis and reducing organ iron loading..
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| ln Vitro |
The fluorescence polarization signal is dose-dependently reduced by VIT-2763, suggesting that VIT-2763 displaces TMR-hepcidin from ferroportin (IC50 of 24 ± 13 nM)[1]. The BLA reporter gene is activated by VIT-2763, with an average EC50 of 140 ± 50 nM, in response to elevated intracellular iron concentrations in HEK293 cells from restricted iron export[1]. Ferroportin is ubiquitinated at 100 nM, which causes ferroportin to internalize and degrade[1].
In vitro, VIT-2763 is a ferroportin inhibitor. It displaces TMR-hepcidin (a fluorescently labeled hepcidin analog) from human ferroportin with an IC50 of 24 nM.. This data confirms its high binding affinity for the ferroportin-hepcidin binding site. By blocking ferroportin, VIT-2763 inhibits the cellular export of iron, which is a key step in the regulation of systemic iron homeostasis. |
| ln Vivo |
In Hbbth3/+ mice, VIT-2763 (30, 100 mg/kg, orally twice daily for 36 days) reduces serum iron levels and prevents hepatic iron loading[1]. The total iron in the liver was not altered by VIT-2763[1]. In Hbbth3/+ mice, oral VIT-2763 (30, 100 mg/kg) taken twice a day for 36 days dramatically corrects anemia and improves RBC parameters. In Hbbth3/+ mice, VIT-2763 reduces the proportion of ROS-positive RBCs from 67% to 30%[1]. In Hbbth3/+ mice, VIT-2763 prolongs RBC life and reduces apoptosis[1].
In vivo, VIT-2763 has been shown to ameliorate anemia, enhance erythropoiesis, and reduce organ iron loading in the Hbbth3/+ beta-thalassemia intermedia disease model.. This mouse model of beta-thalassemia exhibits ineffective erythropoiesis, anemia, and secondary iron overload. VIT-2763 acts as an oral ferroportin inhibitor, blocking iron export from macrophages and enterocytes. This restricts iron availability for the production of hemoglobin, which in the context of beta-thalassemia can reduce the oxidative stress and red blood cell destruction that drive the pathology. |
| Enzyme Assay |
The standard in vitro protocol for assessing ferroportin binding and inhibition is a fluorescence polarization (FP) assay. Recombinant human ferroportin protein (purified and reconstituted in nanodiscs) is incubated with a TMR-labeled hepcidin probe (TMR-hepcidin, 1 nM) for 30 minutes at room temperature in a 384-well plate. Varying concentrations of VIT-2763 (from 0.1 nM to 10 uM) are added to compete for the binding site. After a 2-hour incubation, fluorescence polarization is measured using a plate reader. The IC50 is determined by fitting the competition curve using a non-linear regression algorithm (IC50 = 24 nM)..
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| Cell Assay |
Cell Viability Assay[1].
Cell Types: J774 cells. Tested Concentrations: 100 nM. Incubation Duration: 10, 20, 40, 60, or 120 minutes. Experimental Results: Induced ferroportin internalization and ubiquitination. For in vitro cellular assays, human monocytic THP-1 cells or primary macrophages are used to model iron export. Cells are seeded in 24-well plates and differentiated into macrophages using phorbol 12-myristate 13-acetate (PMA, 100 nM) for 48 hours. The cells are then loaded with iron by incubation with ferric ammonium citrate (100 uM) for 24 hours. The medium is replaced with fresh medium containing VIT-2763 at concentrations ranging from 0.1 nM to 10 uM. After 6 hours, the culture supernatant is collected, and the amount of iron released from the cells (ferroportin-mediated export) is measured using a colorimetric ferrozine-based iron assay. The reduction in iron export is calculated, and the IC50 is determined. Intracellular iron levels can be measured by lysing the cells and using the same ferrozine assay after deproteinization. |
| Animal Protocol |
Animal/Disease Models: Hbbth3/+ mice[1].
Doses: 30, 100 mg/kg. Route of Administration: Orally twice (two times) daily for 36 days. Experimental Results: Dramatically diminished serum iron levels by 77% (30 mg/kg) and 84% (100 mg/kg), Dramatically increased Hb levels (as of day 8 of treatment), RBC counts, mean corpuscular Hb concentration (MCHC), and Dramatically lowered reticulocyte counts, mean corpuscular Hb (MCH), mean corpuscular volume (MCV), and RBC distribution width (RDW) in Hbbth3/+ mice, as compared with the Hbbth3/+ vehicle group. An in vivo protocol for VIT-2763 uses the Hbbth3/+ beta-thalassemia intermedia mouse model (also known as the thalassemic or th3/+ mouse). Mice (8-12 weeks old, male and female) are randomized into treatment groups. VIT-2763 is formulated in a suitable vehicle (e.g., 5% DMSO/40% PEG300/5% Tween-80/50% ddH2O) and administered orally by gavage at doses of 1, 3, and 10 mg/kg twice daily (BID) for 4 weeks. Blood samples are collected weekly via retro-orbital bleeding for a complete blood count (CBC) analysis. Hemoglobin (Hb) levels, red blood cell (RBC) counts, and reticulocyte counts are measured. At the end of the study, the spleen weight (an indicator of extramedullary erythropoiesis) is measured. Livers are harvested and digested to measure tissue iron content (ug Fe/g tissue) using inductively coupled plasma mass spectrometry (ICP-MS). Kidney function markers (BUN, creatinine) are also measured. The compound should improve anemia, reduce reticulocytosis, and decrease liver iron loading.. |
| ADME/Pharmacokinetics |
Detailed pharmacokinetic data for VIT-2763 is not provided. However, it is described as an oral small-molecule inhibitor, indicating it is designed for oral administration and absorption.. A standard PK study in mice would involve oral gavage (10 mg/kg) and intravenous (1 mg/kg) administration of VIT-2763. Serial blood samples are collected at 0, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours post-dose. Plasma concentrations are measured by LC-MS/MS. Key parameters including T1/2, Cmax, AUC, clearance (Cl), and oral bioavailability (F%) would be calculated. The compound is likely metabolized by the liver, possibly via CYP450 enzymes.
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| Toxicity/Toxicokinetics |
Specific toxicological data for VIT-2763 is not available. As a ferroportin inhibitor that blocks iron export, the primary safety concern is the potential for iron accumulation in tissues (such as the liver, spleen, and heart) due to the blockade of macrophage and enterocyte iron release. Standard safety assessment would include a 28-day repeat-dose oral toxicity study in rats and dogs to determine the No-Observed-Adverse-Effect Level (NOAEL). Key endpoints would include histological examination of the liver, spleen, and heart for iron deposition (Perls‘ Prussian blue staining). Serum ferritin and liver function tests (ALT, AST) would also be monitored. An in vitro hERG channel inhibition test would be performed to assess the risk of cardiac QT prolongation.
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| References | |
| Additional Infomation |
Vamifeport is being investigated for the treatment of beta-thalassemia.
VIT-2763 (also known as Vamifeport) is an investigational drug and has not yet received regulatory approval for clinical use. It is currently in clinical development for the treatment of beta-thalassemia and other diseases of iron overload. VIT-2763 is a first-in-class, oral ferroportin inhibitor that works by blocking the binding of hepcidin to ferroportin, effectively mimicking the effects of hepcidin to limit iron availability.. It represents a novel therapeutic approach for diseases characterized by ineffective erythropoiesis and iron loading, offering an alternative to conventional iron chelation therapy. |
| Molecular Formula |
C21H21FN6O2
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| Molecular Weight |
408.428847074509
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| Exact Mass |
408.171
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| CAS # |
2095668-10-1
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| PubChem CID |
129052159
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| Appearance |
Off-white to light yellow solid powder
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| LogP |
1.9
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
9
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| Heavy Atom Count |
30
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| Complexity |
556
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| Defined Atom Stereocenter Count |
0
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| SMILES |
FC1=CC=CN=C1CNC(C1=COC(CCNCCC2=NC3C=CC=CC=3N2)=N1)=O
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| InChi Key |
KNYVRFXIVWUGBZ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C21H21FN6O2/c22-14-4-3-9-24-17(14)12-25-21(29)18-13-30-20(28-18)8-11-23-10-7-19-26-15-5-1-2-6-16(15)27-19/h1-6,9,13,23H,7-8,10-12H2,(H,25,29)(H,26,27)
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| Chemical Name |
2-[2-[2-(1H-benzimidazol-2-yl)ethylamino]ethyl]-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamide
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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: 83.33 mg/mL (204.03 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (5.09 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 (5.09 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4484 mL | 12.2420 mL | 24.4840 mL | |
| 5 mM | 0.4897 mL | 2.4484 mL | 4.8968 mL | |
| 10 mM | 0.2448 mL | 1.2242 mL | 2.4484 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.
Link: https://clinicaltrials.gov/ct2/show/NCT07332091
Conditions:Homeostatic Iron Regulator Gene-related Hereditary HemochromatosisLink: https://clinicaltrials.gov/ct2/show/NCT06996184
Conditions:Healthy VolunteersLink: https://clinicaltrials.gov/ct2/show/NCT04817670
Conditions:Sickle Cell DiseaseProducts are for research use only; We do not sell to patients
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