E-4031

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

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
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC21H27N3O3S
Molar mass401.53 g·mol−1
3D model (JSmol)
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)

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 IKr 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 IKr in myocardial cells prolongs the cardiac action potential and thus prolongs the QT-interval.[7][14] In non-cardiac cells, blocking Ikr 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
  1. Kim I, Boyle KM, Carroll JL (April 2005). "Postnatal development of E-4031-sensitive potassium current in rat carotid chemoreceptor cells". Journal of Applied Physiology. 98 (4): 1469–77. doi:10.1152/japplphysiol.01254.2003. PMID 15591286.
  2. Oinuma H, Miyake K, Yamanaka M, Nomoto K, Katoh H, Sawada K, Shino M, Hamano S (March 1990). "4'-[(4-Piperidyl)carbonyl]methanesulfonanilides as potent, selective, bioavailable class III antiarrhythmic agents". Journal of Medicinal Chemistry. 33 (3): 903–5. doi:10.1021/jm00165a003. PMID 2308138.
  3. Gerlach AC, Stoehr SJ, Castle NA (January 2010). "Pharmacological removal of human ether-à-go-go-related gene potassium channel inactivation by 3-nitro-N-(4-phenoxyphenyl) benzamide (ICA-105574)". Molecular Pharmacology. 77 (1): 58–68. doi:10.1124/mol.109.059543. PMID 19805508. S2CID 20582680.
  4. Perrin MJ, Subbiah RN, Vandenberg JI, Hill AP (2008). "Human ether-a-go-go related gene (hERG) K+ channels: function and dysfunction". Progress in Biophysics and Molecular Biology. 98 (2–3): 137–48. doi:10.1016/j.pbiomolbio.2008.10.006. PMID 19027781.
  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 Archiv. 434 (1): 1–10. doi:10.1007/s004240050356. PMID 9094250. S2CID 10233500.
  6. Sanguinetti MC, Jurkiewicz NK (July 1990). "Two components of cardiac delayed rectifier K+ current. Differential sensitivity to block by class III antiarrhythmic agents". The Journal of General Physiology. 96 (1): 195–215. doi:10.1085/jgp.96.1.195. PMC 2228985. PMID 2170562.
  7. Spector PS, Curran ME, Keating MT, Sanguinetti MC (March 1996). "Class III antiarrhythmic drugs block HERG, a human cardiac delayed rectifier K+ channel. Open-channel block by methanesulfonanilides". Circulation Research. 78 (3): 499–503. doi:10.1161/01.res.78.3.499. PMID 8593709.
  8. Lees-Miller JP, Duan Y, Teng GQ, Duff HJ (February 2000). "Molecular determinant of high-affinity dofetilide binding to HERG1 expressed in Xenopus oocytes: involvement of S6 sites". Molecular Pharmacology. 57 (2): 367–74. PMID 10648647.
  9. Mitcheson JS, Chen J, Lin M, Culberson C, Sanguinetti MC (October 2000). "A structural basis for drug-induced long QT syndrome". Proceedings of the National Academy of Sciences of the United States of America. 97 (22): 12329–33. Bibcode:2000PNAS...9712329M. doi:10.1073/pnas.210244497. PMC 17341. PMID 11005845.
  10. Kamiya K, Mitcheson JS, Yasui K, Kodama I, Sanguinetti MC (August 2001). "Open channel block of HERG K(+) channels by vesnarinone". Molecular Pharmacology. 60 (2): 244–53. doi:10.1124/mol.60.2.244. PMID 11455010.
  11. Sánchez-Chapula JA, Navarro-Polanco RA, Culberson C, Chen J, Sanguinetti MC (June 2002). "Molecular determinants of voltage-dependent human ether-a-go-go related gene (HERG) K+ channel block". The Journal of Biological Chemistry. 277 (26): 23587–95. doi:10.1074/jbc.M200448200. PMID 11960982. S2CID 25655188.
  12. Sănchez-Chapula JA, Ferrer T, Navarro-Polanco RA, Sanguinetti MC (May 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". Molecular Pharmacology. 63 (5): 1051–8. doi:10.1124/mol.63.5.1051. PMID 12695533.
  13. Perry M, de Groot MJ, Helliwell R, Leishman D, Tristani-Firouzi M, Sanguinetti MC, Mitcheson J (August 2004). "Structural determinants of HERG channel block by clofilium and ibutilide". Molecular Pharmacology. 66 (2): 240–9. doi:10.1124/mol.104.000117. PMID 15266014. S2CID 7974939.
  14. Wettwer E, Grundke M, Ravens U (November 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". Cardiovascular Research. 26 (11): 1145–52. doi:10.1093/cvr/26.11.1145. PMID 1291093.
  15. Okada Y, Ogawa S, Sadanaga T, Mitamura H (January 1996). "Assessment of reverse use-dependent blocking actions of class III antiarrhythmic drugs by 24-hour Holter electrocardiography". Journal of the American College of Cardiology. 27 (1): 84–9. doi:10.1016/0735-1097(95)00424-6. PMID 8522715.
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