GW-4869 HCl | CAS#6823-69-4 | neutral sphingomyelinases inhibitor

MedKoo Cat#: 555211 | Name: GW-4869 HCl

Description:

WARNING: This product is for research use only, not for human or veterinary use.

GW-4869 is a cell-permeable, non-competitive inhibitor of neutral sphingomyelinases (IC50 = 1 μM). It inhibits TNF-α-mediated sphingomyelin hydrolysis (100% inhibition at 20 μM). GW4869 is cytotoxic to high phosphatidylserine-expressing myeloma cells. Blockade of exosome generation with GW4869 dampens the sepsis-induced inflammation and cardiac dysfunction.

Chemical Structure

GW-4869 HCl

CAS#6823-69-4 (2HCl)

Theoretical Analysis

MedKoo Cat#: 555211

Name: GW-4869 HCl

CAS#: 6823-69-4 (2HCl)

Chemical Formula: C30H30Cl2N6O2

Exact Mass: 0.0000

Molecular Weight: 577.51

Elemental Analysis: C, 62.39; H, 5.24; Cl, 12.28; N, 14.55; O, 5.54

Price and Availability

Size	Price	Availability
100mg	USD 1,450.00	2 Weeks
200mg	USD 2,050.00	2 Weeks
500mg	USD 3,050.00	2 Weeks
1g	USD 4,650.00	2 Weeks

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Related CAS #

6823-69-4 (2HCl) 475570-61-7 (free base)

Synonym

GW4869; GW-4869; GW 4869; GW554869A; GW-554869A; GW 554869A; GW69A; GW-69A; GW 69A; GW-4869 HCl; GW-4869 dihydrochloride

IUPAC/Chemical Name

(2E,2'E)-3,3'-(1,4-phenylene)bis(N-(4-(4,5-dihydro-1H-imidazol-2-yl)phenyl)acrylamide) dihydrochloride

InChi Key

NSFKAZDTKIKLKT-CLEIDKRQSA-N

InChi Code

InChI=1S/C30H28N6O2.2ClH/c37-27(35-25-11-7-23(8-12-25)29-31-17-18-32-29)15-5-21-1-2-22(4-3-21)6-16-28(38)36-26-13-9-24(10-14-26)30-33-19-20-34-30;;/h1-16H,17-20H2,(H,31,32)(H,33,34)(H,35,37)(H,36,38);2*1H/b15-5+,16-6+;;

SMILES Code

O=C(/C=C/C1=CC=C(C=C1)/C=C/C(NC2=CC=C(C=C2)C3=NCCN3)=O)NC4=CC=C(C=C4)C5=NCCN5.[H]Cl.[H]Cl

Appearance

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

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

Product Data

Product Data

Instruction

View handling instruction

Biological target:

GW4869 is a noncompetitive neutral sphingomyelinase (N-SMase) inhibitor with an IC50 of 1 μM. GW4869 is an inhibitor of exosome biogenesis/release.

In vitro activity:

Treatment with GW4869 dramatically reduced the number of ZIKV-positive astrocytes in the infected cultures (Fig. 6f–j). GW4869 treatment also dramatically decreased ZIKV RNA in the supernatants and reduced viral plaque numbers in PFA (Fig. 6k–m). Similarly, treatment with GW4869 significantly decreased EV numbers in ZIKV MR766 strain-infected astrocytes (Fig. 7a and b). GW4869 reduced the levels of Flotillin-2 and tTG (Tissue transglutaminase, another EV marker) in EV lysates (Fig. 7c), suggesting that GW4869 effectively reduces EVs in infected astrocytes. GW4869 treatment markedly decreased ZIKV RNA in infected astrocytes (Fig. 7d) and in supernatants (Fig. 7e). GW4869 treatment also dramatically decreased viral plaque numbers in PFA (Fig. 7f). Together, these data suggest that GW4869 is an effective inhibitor for ZIKV infection in astrocytes. Reference: Cell Discov. 2018 Apr 24;4:19. https://pubmed.ncbi.nlm.nih.gov/29707233/

In vivo activity:

Circulating IL-1β was significantly reduced (47% decrease; Figure XIIA in the online-only Data Supplement) in the plasma of Apoe−/−/Smpd3+/+ mice treated by GW4869 in comparison with vehicle-treated mice and in the plasma of Apoe−/−/Smpd3fro/fro mice (57% decrease; Figure XIIB in the online-only Data Supplement). Likewise, the expression of VCAM-1, IL-1β, IL-6, and TNF-α mRNAs was reduced in aortas of mice injected with GW4869 (Figure XIII in the online-only Data Supplement), together with a decreased ceramide content (around 30%; Figure XIV in the online-only Data Supplement). Finally, the number of MoMa-2/IL-1β positive cells was decreased in the aortic sinus of mice treated by GW4869 (Figure 5A and 5B) and in Apoe−/−/Smpd3fro/fro mice (Figure 5C and 5D). Altogether, these data indicated that nSMase2 inhibition decreases vascular inflammation by reducing the recruitment of monocytes to endothelium and macrophage M1 differentiation. Reference: Arterioscler Thromb Vasc Biol. 2018 Jul;38(7):1479-1492. https://pubmed.ncbi.nlm.nih.gov/29794115/

	Solvent	mg/mL	mM
Solubility
	DMSO	0.9	1.54

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 577.51 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.

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. Peng Y, Zhao M, Hu Y, Guo H, Zhang Y, Huang Y, Zhao L, Chai Y, Wang Z. Blockade of exosome generation by GW4869 inhibits the education of M2 macrophages in prostate cancer. BMC Immunol. 2022 Aug 8;23(1):37. doi: 10.1186/s12865-022-00514-3. PMID: 35941539; PMCID: PMC9361607. 2. Huang Y, Li Y, Zhang H, Zhao R, Jing R, Xu Y, He M, Peer J, Kim YC, Luo J, Tong Z, Zheng J. Zika virus propagation and release in human fetal astrocytes can be suppressed by neutral sphingomyelinase-2 inhibitor GW4869. Cell Discov. 2018 Apr 24;4:19. doi: 10.1038/s41421-018-0017-2. PMID: 29707233; PMCID: PMC5913238. 3. Chen J, Zhou R, Liang Y, Fu X, Wang D, Wang C. Blockade of lncRNA-ASLNCS5088-enriched exosome generation in M2 macrophages by GW4869 dampens the effect of M2 macrophages on orchestrating fibroblast activation. FASEB J. 2019 Nov;33(11):12200-12212. doi: 10.1096/fj.201901610. Epub 2019 Aug 20. Erratum in: FASEB J. 2020 Jun 19;: Erratum in: FASEB J. 2020 Aug;34(8):11307-11310. PMID: 31373848; PMCID: PMC6902732. 4. Lallemand T, Rouahi M, Swiader A, Grazide MH, Geoffre N, Alayrac P, Recazens E, Coste A, Salvayre R, Nègre-Salvayre A, Augé N. nSMase2 (Type 2-Neutral Sphingomyelinase) Deficiency or Inhibition by GW4869 Reduces Inflammation and Atherosclerosis in Apoe-/- Mice. Arterioscler Thromb Vasc Biol. 2018 Jul;38(7):1479-1492. doi: 10.1161/ATVBAHA.118.311208. Epub 2018 May 24. PMID: 29794115; PMCID: PMC6039418.

In vitro protocol:

In vivo protocol:

1. Chen J, Zhou R, Liang Y, Fu X, Wang D, Wang C. Blockade of lncRNA-ASLNCS5088-enriched exosome generation in M2 macrophages by GW4869 dampens the effect of M2 macrophages on orchestrating fibroblast activation. FASEB J. 2019 Nov;33(11):12200-12212. doi: 10.1096/fj.201901610. Epub 2019 Aug 20. Erratum in: FASEB J. 2020 Jun 19;: Erratum in: FASEB J. 2020 Aug;34(8):11307-11310. PMID: 31373848; PMCID: PMC6902732. 2. Lallemand T, Rouahi M, Swiader A, Grazide MH, Geoffre N, Alayrac P, Recazens E, Coste A, Salvayre R, Nègre-Salvayre A, Augé N. nSMase2 (Type 2-Neutral Sphingomyelinase) Deficiency or Inhibition by GW4869 Reduces Inflammation and Atherosclerosis in Apoe-/- Mice. Arterioscler Thromb Vasc Biol. 2018 Jul;38(7):1479-1492. doi: 10.1161/ATVBAHA.118.311208. Epub 2018 May 24. PMID: 29794115; PMCID: PMC6039418.

1: Sang L, Wang X, Zhao X. Mifepristone Inhibits the Migration of Cervical Cancer Cells by Inhibiting Exocrine Secretion. Pharmacology. 2018 Apr 5;101(5-6):322-329. doi: 10.1159/000488356. [Epub ahead of print] PubMed PMID: 29621762. 2: Lee HY, Chen CK, Ho CM, Lee SS, Chang CY, Chen KJ, Jou YS. EIF3C-enhanced exosome secretion promotes angiogenesis and tumorigenesis of human hepatocellular carcinoma. Oncotarget. 2018 Jan 11;9(17):13193-13205. doi: 10.18632/oncotarget.24149. eCollection 2018 Mar 2. PubMed PMID: 29568350; PubMed Central PMCID: PMC5862571. 3: Yang L, Niu F, Yao H, Liao K, Chen X, Kook Y, Ma R, Hu G, Buch S. Exosomal miR-9 Released from HIV Tat Stimulated Astrocytes Mediates Microglial Migration. J Neuroimmune Pharmacol. 2018 Mar 1. doi: 10.1007/s11481-018-9779-4. [Epub ahead of print] PubMed PMID: 29497921. 4: Panigrahi GK, Praharaj PP, Peak TC, Long J, Singh R, Rhim JS, Elmageed ZYA, Deep G. Hypoxia-induced exosome secretion promotes survival of African-American and Caucasian prostate cancer cells. Sci Rep. 2018 Mar 1;8(1):3853. doi: 10.1038/s41598-018-22068-4. PubMed PMID: 29497081; PubMed Central PMCID: PMC5832762. 5: Sobue A, Ito N, Nagai T, Shan W, Hada K, Nakajima A, Murakami Y, Mouri A, Yamamoto Y, Nabeshima T, Saito K, Yamada K. Astroglial major histocompatibility complex class I following immune activation leads to behavioral and neuropathological changes. Glia. 2018 May;66(5):1034-1052. doi: 10.1002/glia.23299. Epub 2018 Jan 30. PubMed PMID: 29380419. 6: Won JH, Kim SK, Shin IC, Ha HC, Jang JM, Back MJ, Kim DK. Dopamine transporter trafficking is regulated by neutral sphingomyelinase 2/ceramide kinase. Cell Signal. 2018 Apr;44:171-187. doi: 10.1016/j.cellsig.2018.01.006. Epub 2018 Jan 9. PubMed PMID: 29329781. 7: Zhou W, Woodson M, Neupane B, Bai F, Sherman MB, Choi KH, Neelakanta G, Sultana H. Exosomes serve as novel modes of tick-borne flavivirus transmission from arthropod to human cells and facilitates dissemination of viral RNA and proteins to the vertebrate neuronal cells. PLoS Pathog. 2018 Jan 4;14(1):e1006764. doi: 10.1371/journal.ppat.1006764. eCollection 2018 Jan. PubMed PMID: 29300779; PubMed Central PMCID: PMC5754134. 8: Menck K, Sönmezer C, Worst TS, Schulz M, Dihazi GH, Streit F, Erdmann G, Kling S, Boutros M, Binder C, Gross JC. Neutral sphingomyelinases control extracellular vesicles budding from the plasma membrane. J Extracell Vesicles. 2017 Sep 26;6(1):1378056. doi: 10.1080/20013078.2017.1378056. eCollection 2017. PubMed PMID: 29184623; PubMed Central PMCID: PMC5699186. 9: Zhang YZ, Liu F, Song CG, Cao XL, Zhang YF, Wu HN, Guo CJ, Li YQ, Zheng QJ, Zheng MH, Han H. Exosomes derived from human umbilical vein endothelial cells promote neural stem cell expansion while maintain their stemness in culture. Biochem Biophys Res Commun. 2018 Jan 1;495(1):892-898. doi: 10.1016/j.bbrc.2017.11.092. Epub 2017 Nov 15. PubMed PMID: 29154990. 10: Chen L, Chen R, Kemper S, Brigstock DR. Pathways of production and delivery of hepatocyte exosomes. J Cell Commun Signal. 2018 Mar;12(1):343-357. doi: 10.1007/s12079-017-0421-7. Epub 2017 Oct 23. PubMed PMID: 29063370; PubMed Central PMCID: PMC5842184. 11: Tan LH, Tan AJ, Ng YY, Chua JJ, Chew WS, Muralidharan S, Torta F, Dutta B, Sze SK, Herr DR, Ong WY. Enriched Expression of Neutral Sphingomyelinase 2 in the Striatum is Essential for Regulation of Lipid Raft Content and Motor Coordination. Mol Neurobiol. 2017 Oct 17. doi: 10.1007/s12035-017-0784-z. [Epub ahead of print] PubMed PMID: 29043558. 12: Niu Z, Pang RTK, Liu W, Li Q, Cheng R, Yeung WSB. Polymer-based precipitation preserves biological activities of extracellular vesicles from an endometrial cell line. PLoS One. 2017 Oct 12;12(10):e0186534. doi: 10.1371/journal.pone.0186534. eCollection 2017. PubMed PMID: 29023592; PubMed Central PMCID: PMC5638560. 13: Kavanagh EL, Lindsay S, Halasz M, Gubbins LC, Weiner-Gorzel K, Guang MHZ, McGoldrick A, Collins E, Henry M, Blanco-Fernández A, Gorman PO, Fitzpatrick P, Higgins MJ, Dowling P, McCann A. Protein and chemotherapy profiling of extracellular vesicles harvested from therapeutic induced senescent triple negative breast cancer cells. Oncogenesis. 2017 Oct 9;6(10):e388. doi: 10.1038/oncsis.2017.82. PubMed PMID: 28991260; PubMed Central PMCID: PMC5668881. 14: Tavakoli Dargani Z, Singla R, Johnson T, Kukreja R, Singla DK. Exosomes derived from embryonic stem cells inhibit doxorubicin and inflammation-induced pyroptosis in muscle cells. Can J Physiol Pharmacol. 2018 Mar;96(3):304-307. doi: 10.1139/cjpp-2017-0340. Epub 2017 Sep 19. PubMed PMID: 28926719. 15: Liu T, Chen G, Sun D, Lei M, Li Y, Zhou C, Li X, Xue W, Wang H, Liu C, Xu J. Exosomes containing miR-21 transfer the characteristic of cisplatin resistance by targeting PTEN and PDCD4 in oral squamous cell carcinoma. Acta Biochim Biophys Sin (Shanghai). 2017 Sep 1;49(9):808-816. doi: 10.1093/abbs/gmx078. PubMed PMID: 28910982. 16: Gon Y, Maruoka S, Inoue T, Kuroda K, Yamagishi K, Kozu Y, Shikano S, Soda K, Lötvall J, Hashimoto S. Selective release of miRNAs via extracellular vesicles is associated with house-dust mite allergen-induced airway inflammation. Clin Exp Allergy. 2017 Dec;47(12):1586-1598. doi: 10.1111/cea.13016. PubMed PMID: 28859242. 17: Cheng Q, Li X, Wang Y, Dong M, Zhan FH, Liu J. The ceramide pathway is involved in the survival, apoptosis and exosome functions of human multiple myeloma cells in vitro. Acta Pharmacol Sin. 2018 Apr;39(4):561-568. doi: 10.1038/aps.2017.118. Epub 2017 Aug 31. PubMed PMID: 28858294. 18: Trajkovic K, Jeong H, Krainc D. Mutant Huntingtin Is Secreted via a Late Endosomal/Lysosomal Unconventional Secretory Pathway. J Neurosci. 2017 Sep 13;37(37):9000-9012. doi: 10.1523/JNEUROSCI.0118-17.2017. Epub 2017 Aug 16. PubMed PMID: 28821645; PubMed Central PMCID: PMC5597981. 19: Cao YL, Zhuang T, Xing BH, Li N, Li Q. Exosomal DNMT1 mediates cisplatin resistance in ovarian cancer. Cell Biochem Funct. 2017 Aug;35(6):296-303. doi: 10.1002/cbf.3276. Epub 2017 Aug 8. PubMed PMID: 28791708. 20: Jung AL, Herkt CE, Schulz C, Bolte K, Seidel K, Scheller N, Sittka-Stark A, Bertrams W, Schmeck B. Legionella pneumophila infection activates bystander cells differentially by bacterial and host cell vesicles. Sci Rep. 2017 Jul 24;7(1):6301. doi: 10.1038/s41598-017-06443-1. PubMed PMID: 28740179; PubMed Central PMCID: PMC5524687.