The Full Wiki

More info on E-4031

E-4031: Wikis

Advertisements

Note: Many of our articles have direct quotes from sources you can cite, within the Wikipedia article! This article doesn't yet, but we're working on it! See more info or our list of citable articles.

Encyclopedia

From Wikipedia, the free encyclopedia

E-4031
Systematic (IUPAC) name
N-[4-[1-[2-(6-Methylpyridin-2-yl)ethyl]piperidine-4-carbonyl]phenyl]

methanesulfonamide

Identifiers
CAS number 113558-89-7
113559-13-0 (dihydrochloride)
ATC code  ?
PubChem 3185
Chemical data
Formula C 21H27N3O3S 
Mol. mass 401.52 g/mol
Synonyms (1-[2-(6-methyl-2-pyridyl)ethyl]-4-(4-methylsulfonyl-aminobenzoyl)piperidine)
Pharmacokinetic data
Bioavailability  ?
Metabolism  ?
Half life  ?
Excretion  ?
Therapeutic considerations
Pregnancy cat.  ?
Legal status
Routes  ?

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

Contents

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

As of yet, 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, 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
  5. ^ 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
  6. ^ Sanguinetti MC, Jurkiewicz NK (1990) Two Components of Cardiac Delayed Rectifier K + Current. J Gen Physiol 96:195-215
  7. ^ 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.
  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
  13. ^ 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
  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
Advertisements

Advertisements






Got something to say? Make a comment.
Your name
Your email address
Message