E-4031

E-4031
Clinical data
Other names	(1-[2-(6-methyl-2-pyridyl)ethyl]-4-(4-methylsulfonyl-aminobenzoyl)piperidine)
Identifiers
	IUPAC name N-[4-[1-[2-(6-Methylpyridin-2-yl)ethyl]piperidine-4-carbonyl]phenyl];
CAS Number	113558-89-7 ; 113559-13-0 (dihydrochloride);
PubChem CID	3185;
IUPHAR/BPS	2605;
ChemSpider	3073;
UNII	1L1K8X5DF9;
ChEMBL	ChEMBL327980;
CompTox Dashboard (EPA)	DTXSID00150458 ;
Chemical and physical data
Formula	C21H27N3O3S
Molar mass	401.53 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES Cc1cccc(n1)CCN2CCC(CC2)C(=O)c3ccc(cc3)NS(=O)(=O)C;
	InChI InChI=1S/C21H27N3O3S/c1-16-4-3-5-19(22-16)12-15-24-13-10-18(11-14-24)21(25)17-6-8-20(9-7-17)23-28(2,26)27/h3-9,18,23H,10-15H2,1-2H3; Key:SRUISGSHWFJION-UHFFFAOYSA-N;
	(verify)

E-4031 is an experimental class III antiarrhythmic drug that blocks potassium channels of the hERG-type.^[1]

Chemistry

E-4031 is a synthetized toxin that is a methanesulfonanilide class III antiarrhythmic drug.^[2]

Target

E-4031 acts on a specific class of voltage-gated potassium channels mainly found in the heart, the hERG channels. hERG channels (Kv11.1) mediate the I_Kr current, which repolarizes the myocardial cells.^[3]^[4] The hERG channel is encoded by ether-a-go-go related gene (hERG).^[5]

Mode of action

E-4031 blocks hERG-type potassium channels ^[5]^[6] by binding to the open channels.^[7] Its structural target within the hERG-channel is unclear, but some other methanesulfonanilide class III antiarrhythmic drugs are known to bind to the S6 domain or C-terminal of the hERG-channel.^[8]^[9]^[10]^[11]^[12]^[13]

Reducing I_Kr in myocardial cells prolongs the cardiac action potential and thus prolongs the QT-interval.^[7]^[14] In non-cardiac cells, blocking I_kr has a different effect: it increases the frequency of action potentials.^[5]

Toxicity

As E-4031 can prolong the QT-interval, it can cause lethal arrhythmias.^[13]

Therapeutic use

E-4031 is solely used for research purposes. So far, one clinical trial has been conducted to test the effect of E-4031 on prolongation of the QT-interval.^[15]

References

^ Kim I, Boyle KM, Carrol JL (2005) Postnatal development of E-4031-sensitive potassium current in rat carotid chemoreceptor cells. J Appl Physiol 98(4):1469-1477.
^ Miyake K, Yamanaka M, Katoh H, Shino M, Hamano S, Nomoto K-I, Oinuma H, Sawada K (1990) 4'-[(4-Piperidyl)carbonyl]methanesulfonanilides as potent, selective, bioavailable class III antiarrhythmic agents. J Med Chem 33, 3, 903
^ Gerlach AC, Stoehr SJ, Castle NA (2009 Oct 5. [Epub ahead of print]) Pharmacological Removal of hERG Potassium Channel Inactivation by ICA-105574.
^ Perrin MJ, Subbiah RN, Vandenberg JI, Hill AP (2008) Human ether-à-go-go related gene (hERG) K+ channels: Function and dysfunction. Prog Biophys Mol Biol 98:137-148
^ ^a ^b ^c Weinsberg F, Bauer CK, Schwarz JR (1997) The class III antiarrhythmic agent E-4031 selectively blocks the inactivating inward-rectifying potassium current in rat anterior pituitary tumour cells (GH3/B6 cells). Pflügers Arch – Eur J Physiol 434:1–10
^ Sanguinetti MC, Jurkiewicz NK (1990) Two Components of Cardiac Delayed Rectifier K + Current. J Gen Physiol 96:195-215
^ ^a ^b Spector PS, Curran ME, Keating MT, Sanguinetti MC (1996) Class III Antiarrhythmic Drugs Block HERG, a Human Cardiac Delayed Rectifier K+ Channel. Circ Res 78:499-503.
^ Lees-Miller JP, Duan Y, Teng GQ, and Duff HJ (2000) Molecular determinant of high-affinity dofetilide binding to HERG1 expressed in Xenopus oocytes: involvement of S6 sites. Mol Pharmacol 57:367–374
^ Mitcheson JS, Chen J, Lin M, Culberson C, and Sanguinetti MC (2000a) A structural basis for drug-induced long QT syndrome. Proc Natl Acad Sci USA 97:12329–12333
^ Kamiya K, Mitcheson JS, Yasui K, Kodama I, and Sanguinetti MC (2001) Open channel block of HERG K_ channels by vesnarinone. Mol Pharmacol 60:244–253
^ Sanchez-Chapula JA, Navarro-Polanco RA, Culberson C, Chen J, and Sanguinetti MC (2002) Molecular determinants of voltage-dependent human ether-a-go-go related gene (HERG) K⁺- channel block. J Biol Chem 277:23587–23595
^ Sanchez-Chapula JA, Ferrer T, Navarro-Polanco RA, and Sanguinetti MC (2003) Voltage-dependent profile of human ether-a-go-go-related gene channel block is influenced by a single residue in the S6 transmembrane domain. Mol Pharmacol 63:1051–1058
^ ^a ^b Perry M, De Groot MJ, Helliwell R, Leishman D, Tristani-Firouzi M, Sanguinetti MC, and Mitcheson J (2004) Structural Determinants of HERG Channel Block by Clofilium and Ibutilide. Mol Pharmacol 66:240–249
^ Wettwer E, Grundke M, Ravins U (1992) Differential effects of the new class III antiarrhythmic agents almokalant, E-4031 and D-sotalol, and of quinidine, on delayed rectifier currents in guinea pig ventricular myocytes. Cardiovasc Res 26(11): 1145-52
^ Okada Y, Ogawa S, Sadanaga T, Mitamura H (1996) Assessment of reverse use-dependent blocking actions of class III antiarrhythmic drugs by 24-hour Holter electrocardiography. J Am Coll Cardiol 27(1): 84-9

[1] Kim I, Boyle KM, Carrol JL (2005) Postnatal development of E-4031-sensitive potassium current in rat carotid chemoreceptor cells. J Appl Physiol 98(4):1469-1477.

[2] Miyake K, Yamanaka M, Katoh H, Shino M, Hamano S, Nomoto K-I, Oinuma H, Sawada K (1990) 4'-[(4-Piperidyl)carbonyl]methanesulfonanilides as potent, selective, bioavailable class III antiarrhythmic agents. J Med Chem 33, 3, 903

[3] Gerlach AC, Stoehr SJ, Castle NA (2009 Oct 5. [Epub ahead of print]) Pharmacological Removal of hERG Potassium Channel Inactivation by ICA-105574.

[4] Perrin MJ, Subbiah RN, Vandenberg JI, Hill AP (2008) Human ether-à-go-go related gene (hERG) K+ channels: Function and dysfunction. Prog Biophys Mol Biol 98:137-148

[Weinsberg-5] Weinsberg F, Bauer CK, Schwarz JR (1997) The class III antiarrhythmic agent E-4031 selectively blocks the inactivating inward-rectifying potassium current in rat anterior pituitary tumour cells (GH3/B6 cells). Pflügers Arch – Eur J Physiol 434:1–10

[6] Sanguinetti MC, Jurkiewicz NK (1990) Two Components of Cardiac Delayed Rectifier K + Current. J Gen Physiol 96:195-215

[Spector-7] Spector PS, Curran ME, Keating MT, Sanguinetti MC (1996) Class III Antiarrhythmic Drugs Block HERG, a Human Cardiac Delayed Rectifier K+ Channel. Circ Res 78:499-503.

[8] Lees-Miller JP, Duan Y, Teng GQ, and Duff HJ (2000) Molecular determinant of high-affinity dofetilide binding to HERG1 expressed in Xenopus oocytes: involvement of S6 sites. Mol Pharmacol 57:367–374

[9] Mitcheson JS, Chen J, Lin M, Culberson C, and Sanguinetti MC (2000a) A structural basis for drug-induced long QT syndrome. Proc Natl Acad Sci USA 97:12329–12333

[10] Kamiya K, Mitcheson JS, Yasui K, Kodama I, and Sanguinetti MC (2001) Open channel block of HERG K_ channels by vesnarinone. Mol Pharmacol 60:244–253

[11] Sanchez-Chapula JA, Navarro-Polanco RA, Culberson C, Chen J, and Sanguinetti MC (2002) Molecular determinants of voltage-dependent human ether-a-go-go related gene (HERG) K⁺- channel block. J Biol Chem 277:23587–23595

[12] Sanchez-Chapula JA, Ferrer T, Navarro-Polanco RA, and Sanguinetti MC (2003) Voltage-dependent profile of human ether-a-go-go-related gene channel block is influenced by a single residue in the S6 transmembrane domain. Mol Pharmacol 63:1051–1058

[Perry-13] Perry M, De Groot MJ, Helliwell R, Leishman D, Tristani-Firouzi M, Sanguinetti MC, and Mitcheson J (2004) Structural Determinants of HERG Channel Block by Clofilium and Ibutilide. Mol Pharmacol 66:240–249

[14] Wettwer E, Grundke M, Ravins U (1992) Differential effects of the new class III antiarrhythmic agents almokalant, E-4031 and D-sotalol, and of quinidine, on delayed rectifier currents in guinea pig ventricular myocytes. Cardiovasc Res 26(11): 1145-52

[15] Okada Y, Ogawa S, Sadanaga T, Mitamura H (1996) Assessment of reverse use-dependent blocking actions of class III antiarrhythmic drugs by 24-hour Holter electrocardiography. J Am Coll Cardiol 27(1): 84-9

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