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| 5mg |
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| 25mg |
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Purity: ≥98%
Neflamapimod (formerly also known as VX-745, VRT-031745 and VD-31745) is a novel, highly potent and selective p38α MAPK inhibitor that may have anti-inflammatory (such as anti-arthritis) properties. It has an IC50 of 10 nM, is 22-fold more selective for the p38α over p38β, and shows no inhibition for the p38γ. In vitro LPS-stimulated HWB production of TNF is inhibited by VX-745 (IC50 = 177 nM). Excellent enzyme selectivity and activity can be seen in VX-745. It also has a good pharmacokinetic profile and shows good in vivo activity in inflammation model organisms.
| Targets |
p38α (IC50 = 10 nM); p38β (IC50 = 220 nM)
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| ln Vitro |
VX-745 selectively inhibits p38α and p38β MAPK with IC50 values of 10 nM and 220 nM, respectively. It does not, however, inhibit p38γ MAPK or a significant number of other kinases with IC50 values greater than 20 M. VX-745 has an IC50 of 56 and 52 nM for IL-1β and TNFα in a human peripheral blood mononuclear cell (PBMC) assay, respectively. The IL-1 and TNFα induced production of IL-6 and IL-8 as well as the LPS and IL-1β-mediated synthesis of COX-2 are both inhibited by VX-745.[1-3] VX-745 (60 nM-20 µM) inhibits bone marrow stromal cells' (BMSCs') production of IL-6 and VEGF without compromising their viability. Additionally, VX-745 prevents BMSCs from secreting IL-6 when TNF-α is present. Inhibiting both multiple myeloma (MM) cell proliferation and IL-6 secretion in BMSCs that is brought on by MM cells adhering to BMSCs suggests that VX-745 can inhibit paracrine MM cell growth in the BM milieu and overcome drug resistance related to cell adhesion.[4]
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| ln Vivo |
VX-745 has an ED50 of 5 mg/kg against adjuvant-induced arthritis (AA) in rats. VX-745 inhibits bone resorption by 93% and inflammation by 56% in AA rats, according to histological results. VX-745 shows a dose-responsive decline in severity score in the traditional cartilage-induced arthritis model. [1-3] When compared to mice that received vehicle treatment, VX-745 (2.5, 5, and 10 mg/kg) improved the inflammatory scores in a type II collagen-induced arthritis (CIA) mouse model by 27%, 31%, and 44%, respectively. Additionally, VX-745 exhibits a 32–39% protection against bone and cartilage erosion according to histological scores. [5]
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| Enzyme Assay |
Using a spectrophotometric coupled-enzyme assay, the IC50 for inhibiting p38α and p38β homologs is determined. A fixed concentration of enzyme (15 nM of p38α or p38β) is incubated with VX-745 in DMSO for 10 min. at 30 °C in 0.1 M HEPES buffer, pH 7.5, containing 10% glycerol, 10 mM MgCl2, 2.5 mM phosphoenolpyruvate, 200 µM NADH, 150 µg/mL pyruvate kinase, 50 µg/mL lactate dehydrogenase, and 200 µM EGF receptor peptide (KRELVEPLTPSGEAPNQALLR). For the p38α and p38β assays, 100 µM and 70 µM ATP, respectively, are used to start the reaction. To track the reaction's progress, the decrease in absorbance at 340 nm is measured. As a function of inhibitor concentration, IC50 is calculated from rate data.
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| Cell Assay |
In 96-well culture plates, BMSCs (5 × 104 cells/well) or MM cells (3 × 104 cells/well) are incubated for 48 hours at 37 °C in the presence or absence of VX-745. The uptake of [3H]-thymidine ([3H]TdR) is used to measure DNA synthesis. During the final eight hours of 48-hour cultures, [3H]TdR (0.5 μCi/well [.0185 MBq]) is pulsed into the cells. By measuring the absorbance of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) dye, the growth inhibition of both MM cells and BMSCs by VX-745 is also determined.
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| Animal Protocol |
Type II collagen-induced arthritis (CIA) mice model (DBA/1J)
2.5, 5, and 10 mg/kg Oral gavage twice daily |
| References |
| Molecular Formula |
C19H9CL2F2N3OS
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|---|---|---|
| Molecular Weight |
436.26
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| Exact Mass |
434.98
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| Elemental Analysis |
C, 52.31; H, 2.08; Cl, 16.25; F, 8.71; N, 9.63; O, 3.67; S, 7.35
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| CAS # |
209410-46-8
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| Related CAS # |
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| Appearance |
Yellow solid powder
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| SMILES |
C1=CC(=C(C(=C1)Cl)C2=C3C=CC(=NN3C=NC2=O)SC4=C(C=C(C=C4)F)F)Cl
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| InChi Key |
VEPKQEUBKLEPRA-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C19H9Cl2F2N3OS/c20-11-2-1-3-12(21)17(11)18-14-5-7-16(25-26(14)9-24-19(18)27)28-15-6-4-10(22)8-13(15)23/h1-9H
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| Chemical Name |
5-(2,6-dichlorophenyl)-2-(2,4-difluorophenyl)sulfanylpyrimido[1,6-b]pyridazin-6-one
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| Synonyms |
VD31745; VX 745; VX745; VRT 031745; VD 31745; VX-745; VRT-031745, VD-31745; VRT031745
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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 |
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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) |
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| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2922 mL | 11.4611 mL | 22.9221 mL | |
| 5 mM | 0.4584 mL | 2.2922 mL | 4.5844 mL | |
| 10 mM | 0.2292 mL | 1.1461 mL | 2.2922 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT05869669 | Recruiting | Drug: Neflamapimod Drug: Placebo |
Dementia With Lewy Bodies | EIP Pharma Inc | May 1, 2023 | Phase 2 |
| NCT03435861 | Completed | Drug: VX-745 Drug: placebo |
Alzheimer Disease | University Hospital, Toulouse | October 8, 2018 | Phase 2 |
| NCT04001517 | Completed | Drug: Neflamapimod | Dementia With Lewy Bodies (DLB) |
EIP Pharma Inc | September 30, 2019 | Phase 2 |
| NCT03402659 | Completed | Drug: neflamapimod Other: placebo |
Alzheimer Disease | EIP Pharma Inc | December 29, 2017 | Phase 2 |
| NCT03980938 | Terminated | Drug: neflamapimod Other: placebo |
Huntington Disease | EIP Pharma Inc | July 8, 2019 | Phase 2 |
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