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

Theoretical Analysis

MedKoo Cat#: 203163
Name: Neflamapimod
CAS#: 209410-46-8
Chemical Formula: C19H9Cl2F2N3OS
Exact Mass: 434.98114
Molecular Weight: 436.26
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
10.0mg USD 90.0 Same Day
25.0mg USD 150.0 Same Day
50.0mg USD 250.0 Same Day
100.0mg USD 450.0 Same Day
200.0mg USD 750.0 Same Day
500.0mg USD 1450.0 Same Day
1.0g USD 2450.0 Same Day
2.0g USD 4650.0 Same Day
5.0g USD 6950.0 Same Day
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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

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 40.93 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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1: Davis T, Brook AJ, Rokicki MJ, Bagley MC, Kipling D. Evaluating the Role of p38 MAPK in the Accelerated Cell Senescence of Werner Syndrome Fibroblasts. Pharmaceuticals (Basel). 2016 Apr 28;9(2). pii: E23. doi: 10.3390/ph9020023. PubMed PMID: 27136566.

2: Alam JJ. Selective Brain-Targeted Antagonism of p38 MAPKα Reduces Hippocampal IL-1β Levels and Improves Morris Water Maze Performance in Aged Rats. J Alzheimers Dis. 2015;48(1):219-27. doi: 10.3233/JAD-150277. PubMed PMID: 26401942.

3: Pradal J, Zuluaga MF, Maudens P, Waldburger JM, Seemayer CA, Doelker E, Gabay C, Jordan O, Allémann E. Intra-articular bioactivity of a p38 MAPK inhibitor and development of an extended-release system. Eur J Pharm Biopharm. 2015 Jun;93:110-7. doi: 10.1016/j.ejpb.2015.03.017. Epub 2015 Mar 30. PubMed PMID: 25836052.

4: McGuire VA, Gray A, Monk CE, Santos SG, Lee K, Aubareda A, Crowe J, Ronkina N, Schwermann J, Batty IH, Leslie NR, Dean JL, O'Keefe SJ, Boothby M, Gaestel M, Arthur JS. Cross talk between the Akt and p38α pathways in macrophages downstream of Toll-like receptor signaling. Mol Cell Biol. 2013 Nov;33(21):4152-65. doi: 10.1128/MCB.01691-12. Epub 2013 Aug 26. PubMed PMID: 23979601; PubMed Central PMCID: PMC3811899.

5: Tsai YR, Wang YJ, Lee MR, Hsu MF, Wang JP. p38 Mitogen-activated protein kinase and extracellular signal-regulated kinase signaling pathways are not essential regulators of formyl peptide-stimulated p47(phox) activation in neutrophils. Eur J Pharmacol. 2013 Feb 15;701(1-3):96-105. doi: 10.1016/j.ejphar.2013.01.003. Epub 2013 Jan 21. PubMed PMID: 23348708.

6: Azevedo R, van Zeeland M, Raaijmakers H, Kazemier B, de Vlieg J, Oubrie A. X-ray structure of p38α bound to TAK-715: comparison with three classic inhibitors. Acta Crystallogr D Biol Crystallogr. 2012 Aug;68(Pt 8):1041-50. doi: 10.1107/S090744491201997X. Epub 2012 Jul 17. PubMed PMID: 22868770.

7: Duffy JP, Harrington EM, Salituro FG, Cochran JE, Green J, Gao H, Bemis GW, Evindar G, Galullo VP, Ford PJ, Germann UA, Wilson KP, Bellon SF, Chen G, Taslimi P, Jones P, Huang C, Pazhanisamy S, Wang YM, Murcko MA, Su MS. The Discovery of VX-745: A Novel and Selective p38α Kinase Inhibitor. ACS Med Chem Lett. 2011 Jul 28;2(10):758-63. doi: 10.1021/ml2001455. eCollection 2011 Oct 13. PubMed PMID: 24900264; PubMed Central PMCID: PMC4018046.

8: Selness SR, Boehm TL, Walker JK, Devadas B, Durley RC, Kurumbail R, Shieh H, Xing L, Hepperle M, Rucker PV, Jerome KD, Benson AG, Marrufo LD, Madsen HM, Hitchcock J, Owen TJ, Christie L, Promo MA, Hickory BS, Alvira E, Naing W, Blevis-Bal R, Devraj RV, Messing D, Schindler JF, Hirsch J, Saabye M, Bonar S, Webb E, Anderson G, Monahan JB. Design, synthesis and activity of a potent, selective series of N-aryl pyridinone inhibitors of p38 kinase. Bioorg Med Chem Lett. 2011 Jul 1;21(13):4059-65. doi: 10.1016/j.bmcl.2011.04.120. Epub 2011 May 13. PubMed PMID: 21640588.

9: Verkaar F, van der Doelen AA, Smits JF, Blankesteijn WM, Zaman GJ. Inhibition of Wnt/β-catenin signaling by p38 MAP kinase inhibitors is explained by cross-reactivity with casein kinase Iδ/ɛ. Chem Biol. 2011 Apr 22;18(4):485-94. doi: 10.1016/j.chembiol.2011.01.015. PubMed PMID: 21513885.

10: Bagley MC, Davis T, Dix MC, Fusillo V, Pigeaux M, Rokicki MJ, Kipling D. Gram-scale synthesis of the p38α MAPK-inhibitor VX-745 for preclinical studies into Werner syndrome. Future Med Chem. 2010 Sep;2(9):1417-27. doi: 10.4155/fmc.10.217. PubMed PMID: 21426137.

11: Chopra P, Kulkarni O, Gupta S, Bajpai M, Kanoje V, Banerjee M, Bansal V, Visaga S, Chatterjee M, Chaira T, Shirumalla RK, Verma AK, Dastidar SG, Sharma G, Ray A. Pharmacological profile of AW-814141, a novel, potent, selective and orally active inhibitor of p38 MAP kinase. Int Immunopharmacol. 2010 Apr;10(4):467-73. doi: 10.1016/j.intimp.2010.01.007. Epub 2010 Jan 20. PubMed PMID: 20093202.

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.

13: Genovese MC. Inhibition of p38: has the fat lady sung? Arthritis Rheum. 2009 Feb;60(2):317-20. doi: 10.1002/art.24264. PubMed PMID: 19180514.

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.

15: Chen MH, Fitzgerald P, Singh SB, O'Neill EA, Schwartz CD, Thompson CM, O'Keefe SJ, Zaller DM, Doherty JB. Synthesis and biological activity of quinolinone and dihydroquinolinone p38 MAP kinase inhibitors. Bioorg Med Chem Lett. 2008 Mar 15;18(6):2222-6. doi: 10.1016/j.bmcl.2006.10.097. Epub 2006 Nov 6. PubMed PMID: 18316187.

16: Bagley MC, Davis T, Dix MC, Rokicki MJ, Kipling D. Rapid synthesis of VX-745: p38 MAP kinase inhibition in Werner syndrome cells. Bioorg Med Chem Lett. 2007 Sep 15;17(18):5107-10. Epub 2007 Jul 13. PubMed PMID: 17659871.

17: Natarajan SR, Wisnoski DD, Thompson JE, O'Neill EA, O'Keefe SJ. p38 MAP kinase inhibitors. Part 3: SAR on 3,4-dihydropyrimido[4,5-d]pyrimidin-2-ones and 3,4-dihydropyrido[4,3-d]pyrimidin-2-ones. Bioorg Med Chem Lett. 2006 Aug 15;16(16):4400-4. Epub 2006 Jun 5. PubMed PMID: 16750629.

18: Wagner G, Laufer S. Small molecular anti-cytokine agents. Med Res Rev. 2006 Jan;26(1):1-62. Review. PubMed PMID: 16283677.

19: Natarajan SR, Doherty JB. P38 MAP kinase inhibitors: evolution of imidazole-based and pyrido-pyrimidin-2-one lead classes. Curr Top Med Chem. 2005;5(10):987-1003. Review. PubMed PMID: 16178742.

20: Foster ML, Halley F, Souness JE. Potential of p38 inhibitors in the treatment of rheumatoid arthritis. Drug News Perspect. 2000 Oct;13(8):488-97. PubMed PMID: 12937622.



Additional Information

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.