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VX-745

Cat. No. M3294
VX-745 Structure
Synonym:

Neflamapimod

Size Price Availability Quantity
5mg USD 50  USD50 In stock
10mg USD 75  USD75 In stock
25mg USD 140  USD140 In stock
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Quality Control & Documentation
Biological Activity

VX-745 is a lead anti-inflammatory candidate, p38 MAPK inhibitor (IC50=10 nM) for the treatment of Rheumatoid arthritis (RA). p38 MAPK is a specific enzyme that regulates the production of IL-1,  IL-2, IL-6, TNFα, chemokines and nitric oxide (NO), as part of acute and chronic inflammatory responses. In vitro, VX-745 was selective for p38 MAPK compared to a large panel of kinases (IC50≥20µM). VX-745 selectively inhibited p38α MAPK (IC50=10 nM), p38β MAPK (IC50 =220 nM) [368149], but not p38γ MAPK (IC50≥20 µM). In addition, cell data for VX-745 provided IC50 values of 56 and 52 nM for IL-1β and TNFα, respectively, and VX-745 blocked IL-6 and IL-8 production induced by IL-1 and TNFα. In a human whole blood assay, IC50 values were 152 and 177 nM for IL-1β and TNFα inhibition, respectively.

Protocol (for reference only)
Cell Experiment
Cell lines Human bone marrow stromal cells (BMSCs) and multiple myeloma (MM) cells
Preparation method Incubating BMSCs (5 × 104 cells/well) or MM cells (3 × 104 cells/well) in 96-well culture plates in the presence or absence of VX-745 for 48 hours at 37 °C. Measuring DNA synthesis by [3H]-thymidine ([3H]TdR) uptake. Cells are pulsed with [3H]TdR (0.5 μCi/well [.0185 MBq]) during the last 8 hours of 48-hour cultures. Measuring 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) dye absorbance to assess growth inhibition of both MM cells and BMSCs by VX-745 .
Concentrations 60 nM - 20 μM, dissolved in DMSO.
Incubation time 48 hours
Animal Experiment
Animal models Type II collagen-induced arthritis (CIA) mice model (DBA/1J)
Formulation Dissolved in 100% polyethylene glycol
Dosages 2.5, 5, and 10 mg/kg
Administration Oral gavage twice daily
Chemical Information
Molecular Weight 436.26
Formula C19H9Cl2F2N3OS
CAS Number 209410-46-8
Solubility (25°C) DMSO 11 mg/mL
Storage Powder          -20°C   3 years ;  4°C   2 years
In solvent       -80°C   6 months ;  -20°C   1 month
Conversion of different model animals based on BSA (PMID: 27057123)
Species Mouse Rat Rabbit Guinea pig Hamster Dog
Weight (kg) 0.02 0.15 1.8 0.4 0.08 10
Body Surface Area (m2) 0.007 0.025 0.15 0.05 0.02 0.5
Km factor 3 6 12 8 5 20
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.

References

[1] John P Duffy, et al. The Discovery of VX-745: A Novel and Selective p38α Kinase Inhibitor

[2] Mark C Bagley, et al. Gram-scale synthesis of the p38α MAPK-inhibitor VX-745 for preclinical studies into Werner syndrome

[3] Mark C Bagley, et al. Rapid synthesis of VX-745: p38 MAP kinase inhibition in Werner syndrome cells

[4] M Bays, et al. Gateways to Clinical Trials

[5] J J Haddad. VX-745. Vertex Pharmaceuticals

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  Catalog
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Keywords: VX-745, Neflamapimod supplier, p38 MAPK, inhibitors, activators


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