GW4064 | CAS#278779-30-9 | agonist of FXR

MedKoo Cat#: 522515 | Name: GW4064

Description:

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

GW-4064 is a selective agonist of FXR (EC50 = 15 nM). It displays no activity at other nuclear receptors, including the retinoic acid receptor, at concentrations up to 1 μM. GW-4064 upregulates adipokine expression in preadipocytes and HepG2 cells. GW4064 could reduce induction of proinflammatory cytokines by LPS in vitro.

Chemical Structure

GW4064

CAS#278779-30-9

Theoretical Analysis

MedKoo Cat#: 522515

Name: GW4064

CAS#: 278779-30-9

Chemical Formula: C28H22Cl3NO4

Exact Mass: 541.0614

Molecular Weight: 542.84

Elemental Analysis: C, 61.95; H, 4.09; Cl, 19.59; N, 2.58; O, 11.79

Price and Availability

Size	Price	Availability
50mg	USD 350.00	2 Weeks
100mg	USD 600.00	2 Weeks
200mg	USD 1,050.00	2 Weeks
500mg	USD 1,850.00	2 Weeks
1g	USD 2,950.00	2 Weeks

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Synonym

GW4064; GW-4064; GW 4064; GW4064X; GW 4064X; GW-4064X;

IUPAC/Chemical Name

3-[2-[2-chloro-4-[[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methoxy]phenyl]ethenyl]-benzoic acid

InChi Key

BYTNEISLBIENSA-MDZDMXLPSA-N

InChi Code

InChI=1S/C28H22Cl3NO4/c1-16(2)27-21(26(32-36-27)25-22(29)7-4-8-23(25)30)15-35-20-12-11-18(24(31)14-20)10-9-17-5-3-6-19(13-17)28(33)34/h3-14,16H,15H2,1-2H3,(H,33,34)/b10-9+

SMILES Code

O=C(O)C1=CC=CC(/C=C/C2=CC=C(OCC3=C(C(C)C)ON=C3C4=C(Cl)C=CC=C4Cl)C=C2Cl)=C1

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, 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

Product Data

Product Data

Instruction

View handling instruction

Biological target:

GW 4064 is a potent FXR agonist with an EC50 of 65 nM.

In vitro activity:

In bone marrow-derived macrophages (BMDMs), administration of GW4064 showed dose-dependent inhibition of NLRP3 inflammasome activation including the production of IL-1β and IL-18 (Fig. 1A and B) without disrupting the priming stage of NLRP3 inflammasome evidenced by the unchanged TNFα production (Fig. 1C). Reference: FEBS Lett. 2017 Sep;591(18):2836-2847. https://pubmed.ncbi.nlm.nih.gov/28787755/

In vivo activity:

The microbial composition in the mice from the BTBR+GW4064 group was more similar to that observed in mice from the BTBR+DMSO group than in those from the C57 mice. The difference analysis of the distance between the BTBR group and the C57 group showed a significant difference (Figures 5E–G). Weighted UniFrac-based 2D PCoA plot showed the BTBR+GW4064 group get close to the C57 group, suggesting that GW4064 treatment reduced the difference in beta diversity between the microbiota in C57 and BTBR mice (Figures 5D, G). Reference: Front Cell Infect Microbiol. 2022 Jun 22;12:911259. https://pubmed.ncbi.nlm.nih.gov/35811667/

	Solvent	mg/mL	mM
Solubility
	DMF	62.5	115.14
	DMSO	76.1	140.14
	DMSO:PBS (pH 7.2) (1:2)	0.3	0.55
	Ethanol	1.0	1.84

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 542.84 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. Xie S, Guo C, Chi Z, Huang B, Wu Y, Wang D, Xia D. A rapid administration of GW4064 inhibits the NLRP3 inflammasome activation independent of farnesoid X receptor agonism. FEBS Lett. 2017 Sep;591(18):2836-2847. doi: 10.1002/1873-3468.12782. Epub 2017 Aug 20. PMID: 28787755. 2. Zhang S, Pan X, Jeong H. GW4064, an agonist of farnesoid X receptor, represses CYP3A4 expression in human hepatocytes by inducing small heterodimer partner expression. Drug Metab Dispos. 2015 May;43(5):743-8. doi: 10.1124/dmd.114.062836. Epub 2015 Feb 27. PMID: 25725071; PMCID: PMC4407707. 3. Liu J, Liu C, Gao Z, Zhou L, Gao J, Luo Y, Liu T, Fan X. GW4064 Alters Gut Microbiota Composition and Counteracts Autism-Associated Behaviors in BTBR T+tf/J Mice. Front Cell Infect Microbiol. 2022 Jun 22;12:911259. doi: 10.3389/fcimb.2022.911259. PMID: 35811667; PMCID: PMC9257030. 4. Cao Y, Xiao Y, Zhou K, Yan J, Wang P, Yan W, Cai W. FXR agonist GW4064 improves liver and intestinal pathology and alters bile acid metabolism in rats undergoing small intestinal resection. Am J Physiol Gastrointest Liver Physiol. 2019 Aug 1;317(2):G108-G115. doi: 10.1152/ajpgi.00356.2017. Epub 2019 Mar 28. PMID: 30920307.

In vitro protocol:

In vivo protocol:

1. Liu J, Liu C, Gao Z, Zhou L, Gao J, Luo Y, Liu T, Fan X. GW4064 Alters Gut Microbiota Composition and Counteracts Autism-Associated Behaviors in BTBR T+tf/J Mice. Front Cell Infect Microbiol. 2022 Jun 22;12:911259. doi: 10.3389/fcimb.2022.911259. PMID: 35811667; PMCID: PMC9257030. 2. Cao Y, Xiao Y, Zhou K, Yan J, Wang P, Yan W, Cai W. FXR agonist GW4064 improves liver and intestinal pathology and alters bile acid metabolism in rats undergoing small intestinal resection. Am J Physiol Gastrointest Liver Physiol. 2019 Aug 1;317(2):G108-G115. doi: 10.1152/ajpgi.00356.2017. Epub 2019 Mar 28. PMID: 30920307.

1: Flesch D, Gabler M, Lill A, Gomez RC, Steri R, Schneider G, Stark H, Schubert-Zsilavecz M, Merk D. Fragmentation of GW4064 led to a highly potent partial farnesoid X receptor agonist with improved drug-like properties. Bioorg Med Chem. 2015 Jul 1;23(13):3490-8. doi: 10.1016/j.bmc.2015.04.035. Epub 2015 Apr 18. PubMed PMID: 25934227. 2: Zhang S, Pan X, Jeong H. GW4064, an agonist of farnesoid X receptor, represses CYP3A4 expression in human hepatocytes by inducing small heterodimer partner expression. Drug Metab Dispos. 2015 May;43(5):743-8. doi: 10.1124/dmd.114.062836. Epub 2015 Feb 27. PubMed PMID: 25725071; PubMed Central PMCID: PMC4407707. 3: Smalley TL Jr, Boggs S, Caravella JA, Chen L, Creech KL, Deaton DN, Kaldor I, Parks DJ. Novel heterocyclic scaffolds of GW4064 as farnesoid X receptor agonists. Bioorg Med Chem Lett. 2015 Jan 15;25(2):280-4. doi: 10.1016/j.bmcl.2014.11.050. Epub 2014 Nov 26. PubMed PMID: 25499883. 4: Xin XM, Zhong MX, Yang GL, Peng Y, Zhang YL, Zhu W. GW4064, a farnesoid X receptor agonist, upregulates adipokine expression in preadipocytes and HepG2 cells. World J Gastroenterol. 2014 Nov 14;20(42):15727-35. doi: 10.3748/wjg.v20.i42.15727. PubMed PMID: 25400456; PubMed Central PMCID: PMC4229537. 5: Yao J, Zhou CS, Ma X, Fu BQ, Tao LS, Chen M, Xu YP. FXR agonist GW4064 alleviates endotoxin-induced hepatic inflammation by repressing macrophage activation. World J Gastroenterol. 2014 Oct 21;20(39):14430-41. doi: 10.3748/wjg.v20.i39.14430. PubMed PMID: 25339829; PubMed Central PMCID: PMC4202371. 6: Singh N, Yadav M, Singh AK, Kumar H, Dwivedi SK, Mishra JS, Gurjar A, Manhas A, Chandra S, Yadav PN, Jagavelu K, Siddiqi MI, Trivedi AK, Chattopadhyay N, Sanyal S. Synthetic FXR agonist GW4064 is a modulator of multiple G protein-coupled receptors. Mol Endocrinol. 2014 May;28(5):659-73. doi: 10.1210/me.2013-1353. Epub 2014 Mar 5. PubMed PMID: 24597548. 7: Ma Y, Huang Y, Yan L, Gao M, Liu D. Synthetic FXR agonist GW4064 prevents diet-induced hepatic steatosis and insulin resistance. Pharm Res. 2013 May;30(5):1447-57. doi: 10.1007/s11095-013-0986-7. Epub 2013 Feb 1. PubMed PMID: 23371517; PubMed Central PMCID: PMC3664363. 8: Li W, Fu J, Cheng F, Zheng M, Zhang J, Liu G, Tang Y. Unbinding pathways of GW4064 from human farnesoid X receptor as revealed by molecular dynamics simulations. J Chem Inf Model. 2012 Nov 26;52(11):3043-52. doi: 10.1021/ci300459k. Epub 2012 Nov 5. PubMed PMID: 23101941. 9: Hoekstra M, van der Sluis RJ, Li Z, Oosterveer MH, Groen AK, Van Berkel TJ. FXR agonist GW4064 increases plasma glucocorticoid levels in C57BL/6 mice. Mol Cell Endocrinol. 2012 Oct 15;362(1-2):69-75. doi: 10.1016/j.mce.2012.05.010. Epub 2012 May 27. PubMed PMID: 22643070. 10: Misawa T, Hayashi H, Makishima M, Sugiyama Y, Hashimoto Y. E297G mutated bile salt export pump (BSEP) function enhancers derived from GW4064: structural development study and separation from farnesoid X receptor-agonistic activity. Bioorg Med Chem Lett. 2012 Jun 15;22(12):3962-6. doi: 10.1016/j.bmcl.2012.04.099. Epub 2012 Apr 30. PubMed PMID: 22583617. 11: Ohno T, Shirakami Y, Shimizu M, Kubota M, Sakai H, Yasuda Y, Kochi T, Tsurumi H, Moriwaki H. Synergistic growth inhibition of human hepatocellular carcinoma cells by acyclic retinoid and GW4064, a farnesoid X receptor ligand. Cancer Lett. 2012 Oct 28;323(2):215-22. doi: 10.1016/j.canlet.2012.04.015. Epub 2012 May 11. PubMed PMID: 22579649. 12: Chiang PC, Thompson DC, Ghosh S, Heitmeier MR. A formulation-enabled preclinical efficacy assessment of a farnesoid X receptor agonist, GW4064, in hamsters and cynomolgus monkeys. J Pharm Sci. 2011 Nov;100(11):4722-33. doi: 10.1002/jps.22664. Epub 2011 Jun 9. PubMed PMID: 21660973. 13: Dwivedi SK, Singh N, Kumari R, Mishra JS, Tripathi S, Banerjee P, Shah P, Kukshal V, Tyagi AM, Gaikwad AN, Chaturvedi RK, Mishra DP, Trivedi AK, Sanyal S, Chattopadhyay N, Ramachandran R, Siddiqi MI, Bandyopadhyay A, Arora A, Lundåsen T, Anakk SP, Moore DD, Sanyal S. Bile acid receptor agonist GW4064 regulates PPARγ coactivator-1α expression through estrogen receptor-related receptor α. Mol Endocrinol. 2011 Jun;25(6):922-32. doi: 10.1210/me.2010-0512. Epub 2011 Apr 14. PubMed PMID: 21493670. 14: Howarth DL, Law SH, Law JM, Mondon JA, Kullman SW, Hinton DE. Exposure to the synthetic FXR agonist GW4064 causes alterations in gene expression and sublethal hepatotoxicity in eleutheroembryo medaka (Oryzias latipes). Toxicol Appl Pharmacol. 2010 Feb 15;243(1):111-21. doi: 10.1016/j.taap.2009.11.022. Epub 2009 Dec 3. PubMed PMID: 19963001; PubMed Central PMCID: PMC2853180. 15: Bass JY, Caldwell RD, Caravella JA, Chen L, Creech KL, Deaton DN, Madauss KP, Marr HB, McFadyen RB, Miller AB, Parks DJ, Todd D, Williams SP, Wisely GB. Substituted isoxazole analogs of farnesoid X receptor (FXR) agonist GW4064. Bioorg Med Chem Lett. 2009 Jun 1;19(11):2969-73. doi: 10.1016/j.bmcl.2009.04.047. Epub 2009 Apr 18. PubMed PMID: 19410460. 16: Feng S, Yang M, Zhang Z, Wang Z, Hong D, Richter H, Benson GM, Bleicher K, Grether U, Martin RE, Plancher JM, Kuhn B, Rudolph MG, Chen L. Identification of an N-oxide pyridine GW4064 analog as a potent FXR agonist. Bioorg Med Chem Lett. 2009 May 1;19(9):2595-8. doi: 10.1016/j.bmcl.2009.03.008. Epub 2009 Mar 9. PubMed PMID: 19328688. 17: Martínez-Fernández P, Hierro L, Jara P, Alvarez L. Knockdown of ATP8B1 expression leads to specific downregulation of the bile acid sensor FXR in HepG2 cells: effect of the FXR agonist GW4064. Am J Physiol Gastrointest Liver Physiol. 2009 May;296(5):G1119-29. doi: 10.1152/ajpgi.90371.2008. Epub 2009 Feb 19. PubMed PMID: 19228886. 18: Liu Y, Binz J, Numerick MJ, Dennis S, Luo G, Desai B, MacKenzie KI, Mansfield TA, Kliewer SA, Goodwin B, Jones SA. Hepatoprotection by the farnesoid X receptor agonist GW4064 in rat models of intra- and extrahepatic cholestasis. J Clin Invest. 2003 Dec;112(11):1678-87. Epub 2003 Nov 17. PubMed PMID: 14623915; PubMed Central PMCID: PMC281645.