Neflamapimod
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MedKoo CAT#: 203163

CAS#: 209410-46-8

Description: Neflamapimod, also known as VX-745, VRT-031745 and VD-31745, is highly potent and selective p38α inhibitor (IC50 = 10 nM). VX-745 blocks TNFα production in LPS-stimulated HWB in vitro (IC50 = 177 nM). VX-745 displays excellent enzyme activity and selectivity, has a favorable pharmacokinetic profile, and demonstrates good in vivo activity in models of inflammation.

Chemical Structure

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Neflamapimod
CAS# 209410-46-8
Product data Instruction

Theoretical Analysis

MedKoo Cat#: 203163
Name: Neflamapimod
CAS#: 209410-46-8
Chemical Formula: C19H9Cl2F2N3OS
Exact Mass: 434.98
Molecular Weight: 436.260
Elemental Analysis: C, 52.31; H, 2.08; Cl, 16.25; F, 8.71; N, 9.63; O, 3.67; S, 7.35

Price and Availability

Size Price Availability Quantity
10mg USD 90 Ready to ship
25mg USD 150 Ready to ship
50mg USD 250 Ready to ship
100mg USD 450 Ready to ship
200mg USD 750 Ready to ship
500mg USD 1650 Ready to ship
1g USD 2950 Ready to ship
2g USD 5250 Ready to ship
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Synonym: VX-745; VX 745; VX745; VRT-031745, VRT 031745; VRT031745; VD-31745; VD 31745; VD31745; Neflamapimod.

IUPAC/Chemical Name: 5-(2,6-Dichlorophenyl)-2-(2,4-difluorophenylsulfanyl)-6H-pyrimido[3,4-b]pyridazin-6-one

InChi Key: VEPKQEUBKLEPRA-UHFFFAOYSA-N

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

SMILES Code: O=C1C(C2=C(Cl)C=CC=C2Cl)=C3C=CC(SC4=CC=C(F)C=C4F)=NN3C=N1

Appearance: Yellow solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

More Info: VX-745 is an antiarthritic Drugs. Its activities and application include:  Myelodysplastic Syndrome Therapy, Oncolytic Drugs, Rheumatoid Arthritis, Treatment of, treatment of musculoskeletal & connective tissue diseases, Antiinflammatory Drugs, p38 Protein Kinase.          

Biological target: Neflamapimod (VX-745) is a blood-brain barrier penetrant and inhibitor of p38α inhibitor with an IC50 for p38α of 10 nM and for p38β of 220 nM.
In vitro activity: First, VX-745 inhibition of p38 MAPK phosphorylation was examined near the peak (hour 16) and trough (hour 4) of its activity (using two different doses: 10 μM and 20 μM) (Fig. 3). Consistent with the rhythmic time course data (Fig. 1), the levels of phospho-p38 MAPK, but not total p38 MAPK, were higher at hour 16 as compared to hour 4 (Fig. 3). However, the fold change in phospho-p38 MAPK levels was greater in Bmal1-dLuc fibroblasts (5X) than in Per2Luc SCN (1.5X) cells. Treatment of Per2Luc SCN cultures with 10 μM or 20 μM VX-745 at hour 4 or 16 had no effect on the total levels of p38 MAPK, but led to a significant reduction (>83%) in phospho-p38 MAPK levels relative to time-matched controls (Fig. 3a). In Bmal1-dLuc fibroblasts, 10 μM and 20 μM VX-745 also had no effect on total levels of p38 MAPK, but led to significant inhibition of p38 MAPK phosphorylation when treatment occurred at hour 16. At hour 4, phospho-p38 MAPK levels were low, and no further reduction occurred upon treatment with 10 or 20 μM VX-745 (Fig. 3b). Reference: BMC Cancer. 2018; 18: 43. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5761097/
In vivo activity: The ELISA signal in the IL-1β assay in the unaffected left brain hemisphere were below the level for noise in the assay (i.e. below LLOQ of 20 pg/mL) in all rats in all groups. However, 9 of 18 animals in the each of the vehicle and 1.5 mg/kg neflamapimod groups and 6 of 18 animals in the 4.5 mg/kg neflamapimod group had quantifiable IL-1β levels above 20 pg/mL in the injured right brain hemisphere, indicating that despite being six weeks from acute the stroke there was still detectable residual inflammation in a substantial percentage of the animals. Quantifiable IL-1β levels ranged from 21.3 pg/mL to 203.5 pg/mL, though all but three rats had levels below 100 pg/mL (S3 Table). The mean±SD IL-1β levels in the right hemisphere was 44.3.3±55.7 pg/ml in the vehicle group, 30.8±25.9 pg/ml in the 1.5 mg/kg neflamapimod group and 28.5±32.4 pg/ml in the 4.5 mg/kg group; with no statistically significant difference between these groups. Reference: PLoS One. 2020; 15(12): e0233073. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717516/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 40.9 93.82
DMF 30.0 68.77
DMF:PBS (pH 7.2) (1:1) 0.5 1.15
Ethanol 0.1 0.23

Preparing Stock Solutions

The following data is based on the product molecular weight 436.26 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Goldsmith CS, Kim SM, Karunarathna N, Neuendorff N, Toussaint LG, Earnest DJ, Bell-Pedersen D. Inhibition of p38 MAPK activity leads to cell type-specific effects on the molecular circadian clock and time-dependent reduction of glioma cell invasiveness. BMC Cancer. 2018 Jan 10;18(1):43. doi: 10.1186/s12885-017-3896-y. Erratum in: BMC Cancer. 2019 Jan 23;19(1):101. PMID: 29316898; PMCID: PMC5761097. 2. Brown KK, Heitmeyer SA, Hookfin EB, Hsieh L, Buchalova M, Taiwo YO, Janusz MJ. P38 MAP kinase inhibitors as potential therapeutics for the treatment of joint degeneration and pain associated with osteoarthritis. J Inflamm (Lond). 2008 Dec 4;5:22. doi: 10.1186/1476-9255-5-22. PMID: 19055838; PMCID: PMC2612656. 3. Alam JJ, Krakovsky M, Germann U, Levy A. Continuous administration of a p38α inhibitor during the subacute phase after transient ischemia-induced stroke in the rat promotes dose-dependent functional recovery accompanied by increase in brain BDNF protein level. PLoS One. 2020 Dec 4;15(12):e0233073. doi: 10.1371/journal.pone.0233073. PMID: 33275615; PMCID: PMC7717516. 4. Belova SP, Mochalova EP, Kostrominova TY, Shenkman BS, Nemirovskaya TL. P38α-MAPK Signaling Inhibition Attenuates Soleus Atrophy during Early Stages of Muscle Unloading. Int J Mol Sci. 2020 Apr 15;21(8):2756. doi: 10.3390/ijms21082756. PMID: 32326654; PMCID: PMC7215762.
In vitro protocol: 1. Goldsmith CS, Kim SM, Karunarathna N, Neuendorff N, Toussaint LG, Earnest DJ, Bell-Pedersen D. Inhibition of p38 MAPK activity leads to cell type-specific effects on the molecular circadian clock and time-dependent reduction of glioma cell invasiveness. BMC Cancer. 2018 Jan 10;18(1):43. doi: 10.1186/s12885-017-3896-y. Erratum in: BMC Cancer. 2019 Jan 23;19(1):101. PMID: 29316898; PMCID: PMC5761097. 2. Brown KK, Heitmeyer SA, Hookfin EB, Hsieh L, Buchalova M, Taiwo YO, Janusz MJ. P38 MAP kinase inhibitors as potential therapeutics for the treatment of joint degeneration and pain associated with osteoarthritis. J Inflamm (Lond). 2008 Dec 4;5:22. doi: 10.1186/1476-9255-5-22. PMID: 19055838; PMCID: PMC2612656.
In vivo protocol: 1. Alam JJ, Krakovsky M, Germann U, Levy A. Continuous administration of a p38α inhibitor during the subacute phase after transient ischemia-induced stroke in the rat promotes dose-dependent functional recovery accompanied by increase in brain BDNF protein level. PLoS One. 2020 Dec 4;15(12):e0233073. doi: 10.1371/journal.pone.0233073. PMID: 33275615; PMCID: PMC7717516. 2. Belova SP, Mochalova EP, Kostrominova TY, Shenkman BS, Nemirovskaya TL. P38α-MAPK Signaling Inhibition Attenuates Soleus Atrophy during Early Stages of Muscle Unloading. Int J Mol Sci. 2020 Apr 15;21(8):2756. doi: 10.3390/ijms21082756. PMID: 32326654; PMCID: PMC7215762.

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12: Bagley MC, Davis T, Dix MC, Fusillo V, Pigeaux M, Rokicki MJ, Kipling D. Microwave-assisted Ullmann C-S bond formation: synthesis of the P38alpha MAPK clinical candidate VX-745. J Org Chem. 2009 Nov 6;74(21):8336-42. doi: 10.1021/jo9017155. PubMed PMID: 19778055.

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14: Brown KK, Heitmeyer SA, Hookfin EB, Hsieh L, Buchalova M, Taiwo YO, Janusz MJ. P38 MAP kinase inhibitors as potential therapeutics for the treatment of joint degeneration and pain associated with osteoarthritis. J Inflamm (Lond). 2008 Dec 4;5:22. doi: 10.1186/1476-9255-5-22. PubMed PMID: 19055838; PubMed Central PMCID: PMC2612656.

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