CE3F4 | CAS#143703-25-7 | Epac1 inhibitor

CE3F4
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WARNING: This product is for research use only, not for human or veterinary use.

MedKoo CAT#: 562758

CAS#: 143703-25-7

Description: CE3F4 is an inhibitor of human exchange protein directly activated by cyclic AMP isoform 1 (Epac1).

Chemical Structure

CE3F4

CAS# 143703-25-7

Product data Instruction

Theoretical Analysis

MedKoo Cat#: 562758
Name: CE3F4
CAS#: 143703-25-7
Chemical Formula: C11H10Br2FNO
Exact Mass: 348.91
Molecular Weight: 351.010
Elemental Analysis: C, 37.64; H, 2.87; Br, 45.53; F, 5.41; N, 3.99; O, 4.56

Price and Availability

Size	Price	Availability	Quantity
5mg	USD 240
10mg	USD 410
50mg	USD 950
Bulk inquiry Welcome, Customer: Please do not inquire quote if your intended use is for a patient since our products are for research use and for chemical synthesis use, not for human use . For in-stock products, we listed price in the web page. You may inquire prices for which sizes were not listed. If no price is listed, this means the product is not in stock at the moment, which may be available via custom synthesis. For cost-effective reason, minimum order of 1g is requested (typically very expensive). The lead time is usually 2-4 months. Quote of less than 1g will not be provided. MedKoo may not offer quote for below reasons: (1) current available synthetic method appears to be extremely expensive which is obviously not affordable to most customers; (2) Key raw material to make the product is temporally not available; (3) DEA controlled substances; (4) the product is under patent protection in customer’s country.

Synonym: CE3F4; CE-3-F-4; CE 3 F 4; CE-3F4; CE 3F4;

IUPAC/Chemical Name: 6-Fluoro-5,7-dibromo-2-methyl-1-formyl-1,2,3,4-tetrahydroquinoline

InChi Key: ZZLQPWXVZCPUGC-UHFFFAOYSA-N

InChi Code: InChI=1S/C11H10Br2FNO/c1-6-2-3-7-9(15(6)5-16)4-8(12)11(14)10(7)13/h4-6H,2-3H2,1H3

SMILES Code: O=CN1C(C)CCC2=C1C=C(Br)C(F)=C2Br

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

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Product Data:

Product Data

Instruction:

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Biological target:	CE3F4 is a selective antagonist of exchange protein directly activated by cAMP (Epac1), with IC50s of 10.7 μM and 66 μM for Epac1 and Epac2(B), respectively.
In vitro activity:	CE3F4, a tetrahydroquinoline analog, prevents Epac1 activation in vitro and in living cultured cells by inhibiting the GEF activity of Epac1. However, the activity of the (R)- and (S)-enantiomers of CE3F4, as well as the ability of CE3F4 and its analogs to inhibit Epac2 GEF activity, have not yet been investigated. In this study, it’s reported that (R)-CE3F4 is a more potent cAMP antagonist than racemic CE3F4 and (S)-CE3F4, inhibiting the GEF activity of Epac1 with 10-times more efficiency than (S)-CE3F4. Epac2, in contrast to Epac1, is activated more efficiently by cAMP than by 8-(4-chlorophenylthio)-2'-O-methyladenosine-3',5'-cyclic monophosphate (007), an Epac-selective cAMP analog. (R)-CE3F4 displays Epac isoform preference, with 10-fold selectivity for Epac1 over Epac2. Deletion of the N-terminal cyclic nucleotide-binding domain of Epac2 does not affect the characteristics of activation of Epac2 by cAMP and by 007, nor its inhibition by CE3F4. Finally, the evaluation of a series of CE3F4 structural analogs as GEF inhibitors allowed identifying structural features that are important for high Epac1 inhibitory activity of CE3F4. It’s concluded that the (R)-enantiomer of CE3F4 is a preferential inhibitor of Epac1 with high potency in the low micromolar range, and it’s suggested that this compound may be a useful pharmacological tool for investigating the functional role of Epac1 in cAMP signaling. Reference: J Biol Chem. 2012 Dec 28;287(53):44192-202. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23139415/
In vivo activity:	The usefulness of CE3F4, an Epac1-selective inhibitor, is examined in the treatment of the arrhythmias in mice. In Epac1 knockout (Epac1-KO) mice, the duration of atrial fibrillation (AF) was shorter than in wild-type mice. In calsequestrin2 knockout mice, Epac1 deficiency resulted in a reduction of ventricular arrhythmia. In both atrial and ventricular myocytes, sarcoplasmic reticulum (SR) Ca2+ leak, a major trigger of arrhythmias, and spontaneous SR Ca2+ release (SCR) were attenuated in Epac1-KO mice. Consistently, CE3F4 treatment significantly prevented AF and ventricular arrhythmia in mice. In addition, the SR Ca2+ leak and SCR were significantly inhibited by CE3F4 treatment in both atrial and ventricular myocytes. Importantly, cardiac function was not significantly affected by a dosage of CE3F4 sufficient to exert anti-arrhythmic effects. Reference: Circ J. 2019 Jan 25;83(2):295-303. https://dx.doi.org/10.1253/circj.CJ-18-0743

Solubility Data

	Solvent	Max Conc. mg/mL	Max Conc. mM
Solubility
	DMSO	50.0	142.45

Preparing Stock Solutions

The following data is based on the product molecular weight 351.01 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:
In vitro protocol:	1. Courilleau D, Bisserier M, Jullian JC, Lucas A, Bouyssou P, Fischmeister R, Blondeau JP, Lezoualc'h F. Identification of a tetrahydroquinoline analog as a pharmacological inhibitor of the cAMP-binding protein Epac. J Biol Chem. 2012 Dec 28;287(53):44192-202. doi: 10.1074/jbc.M112.422956. Epub 2012 Nov 8. PMID: 23139415; PMCID: PMC3531735. 2. Courilleau D, Bouyssou P, Fischmeister R, Lezoualc'h F, Blondeau JP. The (R)-enantiomer of CE3F4 is a preferential inhibitor of human exchange protein directly activated by cyclic AMP isoform 1 (Epac1). Biochem Biophys Res Commun. 2013 Oct 25;440(3):443-8. doi: 10.1016/j.bbrc.2013.09.107. Epub 2013 Oct 4. PMID: 24099776.
In vivo protocol:	1. Prajapati R, Fujita T, Suita K, Nakamura T, Cai W, Hidaka Y, Umemura M, Yokoyama U, Knollmann BC, Okumura S, Ishikawa Y. Usefulness of Exchanged Protein Directly Activated by cAMP (Epac)1-Inhibiting Therapy for Prevention of Atrial and Ventricular Arrhythmias in Mice. Circ J. 2019 Jan 25;83(2):295-303. doi: 10.1253/circj.CJ-18-0743. Epub 2018 Dec 6. PMID: 30518738. 2. Zhang MX, Zheng JK, Wang WW, Kong FQ, Wu XX, Jiang JK, Pan JX. Exchange-protein activated by cAMP (EPAC) regulates L-type calcium channel in atrial fibrillation of heart failure model. Eur Rev Med Pharmacol Sci. 2019 Mar;23(5):2200-2207. doi: 10.26355/eurrev_201903_17267. PMID: 30915767.

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1: Sonawane YA, Zhu Y, Garrison JC, Ezell EL, Zahid M, Cheng X, Natarajan A. Structure-Activity Relationship Studies with Tetrahydroquinoline Analogs as EPAC Inhibitors. ACS Med Chem Lett. 2017 Oct 2;8(11):1183-1187. doi: 10.1021/acsmedchemlett.7b00358. eCollection 2017 Nov 9. PubMed PMID: 29375750; PubMed Central PMCID: PMC5774307.

2: Brouwer S, Hoffmeister T, Gresch A, Schönhoff L, Düfer M. Resveratrol Influences Pancreatic Islets by Opposing Effects on Electrical Activity and Insulin Release. Mol Nutr Food Res. 2018 Mar;62(5). doi: 10.1002/mnfr.201700902. PubMed PMID: 29341416.

3: Yu X, Zhang Q, Zhao Y, Schwarz BJ, Stallone JN, Heaps CL, Han G. Activation of G protein-coupled estrogen receptor 1 induces coronary artery relaxation via Epac/Rap1-mediated inhibition of RhoA/Rho kinase pathway in parallel with PKA. PLoS One. 2017 Mar 9;12(3):e0173085. doi: 10.1371/journal.pone.0173085. eCollection 2017. PubMed PMID: 28278256; PubMed Central PMCID: PMC5344336.

4: Jansen SR, Poppinga WJ, de Jager W, Lezoualc'h F, Cheng X, Wieland T, Yarwood SJ, Gosens R, Schmidt M. Epac1 links prostaglandin E2 to β-catenin-dependent transcription during epithelial-to-mesenchymal transition. Oncotarget. 2016 Jul 19;7(29):46354-46370. doi: 10.18632/oncotarget.10128. PubMed PMID: 27344171; PubMed Central PMCID: PMC5216803.

5: Pratt EP, Salyer AE, Guerra ML, Hockerman GH. Ca2+ influx through L-type Ca2+ channels and Ca2+-induced Ca2+ release regulate cAMP accumulation and Epac1-dependent ERK 1/2 activation in INS-1 cells. Mol Cell Endocrinol. 2016 Jan 5;419:60-71. doi: 10.1016/j.mce.2015.09.034. Epub 2015 Oct 3. PubMed PMID: 26435461; PubMed Central PMCID: PMC4684454.

6: Domínguez-Rodríguez A, Ruiz-Hurtado G, Sabourin J, Gómez AM, Alvarez JL, Benitah JP. Proarrhythmic effect of sustained EPAC activation on TRPC3/4 in rat ventricular cardiomyocytes. J Mol Cell Cardiol. 2015 Oct;87:74-8. doi: 10.1016/j.yjmcc.2015.07.002. Epub 2015 Jul 26. PubMed PMID: 26219954.

7: Laurent AC, Bisserier M, Lucas A, Tortosa F, Roumieux M, De Régibus A, Swiader A, Sainte-Marie Y, Heymes C, Vindis C, Lezoualc'h F. Exchange protein directly activated by cAMP 1 promotes autophagy during cardiomyocyte hypertrophy. Cardiovasc Res. 2015 Jan 1;105(1):55-64. doi: 10.1093/cvr/cvu242. Epub 2014 Nov 19. PubMed PMID: 25411381.

8: Brown LM, Rogers KE, McCammon JA, Insel PA. Identification and validation of modulators of exchange protein activated by cAMP (Epac) activity: structure-function implications for Epac activation and inhibition. J Biol Chem. 2014 Mar 21;289(12):8217-30. doi: 10.1074/jbc.M114.548636. Epub 2014 Feb 4. PubMed PMID: 24497631; PubMed Central PMCID: PMC3961650.

9: Courilleau D, Bouyssou P, Fischmeister R, Lezoualc'h F, Blondeau JP. The (R)-enantiomer of CE3F4 is a preferential inhibitor of human exchange protein directly activated by cyclic AMP isoform 1 (Epac1). Biochem Biophys Res Commun. 2013 Oct 25;440(3):443-8. doi: 10.1016/j.bbrc.2013.09.107. Epub 2013 Oct 4. PubMed PMID: 24099776.

10: Courilleau D, Bisserier M, Jullian JC, Lucas A, Bouyssou P, Fischmeister R, Blondeau JP, Lezoualc'h F. Identification of a tetrahydroquinoline analog as a pharmacological inhibitor of the cAMP-binding protein Epac. J Biol Chem. 2012 Dec 28;287(53):44192-202. doi: 10.1074/jbc.M112.422956. Epub 2012 Nov 8. PubMed PMID: 23139415; PubMed Central PMCID: PMC3531735.

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