View source for E-4031

{{Drugbox
| IUPAC_name        = ''N''-[4-[1-[2-(6-Methylpyridin-2-yl)ethyl]piperidine-4-carbonyl]phenyl]
methanesulfonamide
| synonyms          = (1-[2-(6-methyl-2-pyridyl)ethyl]-4-(4-methylsulfonyl-aminobenzoyl)piperidine)
| image             = E-4031.png
| alt               = 
| CAS_number        = 113558-89-7
| CAS_supplemental  = <br>113559-13-0 (dihydrochloride)
| ATCvet            = 
| ATC_prefix        = <!-- 'none' if uncategorised -->
| ATC_suffix        = 
| PubChem           = 3185
| DrugBank          = 
| C=21|H=27|N=3|O=3|S=1
| molecular_weight  = 401.52 g/mol
| bioavailability   = 
| protein_bound     = 
| metabolism        = 
| elimination_half-life = 
| excretion         = 
| pregnancy_AU      =  <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_US      =  <!-- A / B            / C / D / X -->
| pregnancy_category=  
| legal_AU =  <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled-->
| legal_CA =  <!-- Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_UK =  <!-- GSL, P, POM, CD, or Class A, B, C -->
| legal_US =  <!-- OTC / Rx-only / Schedule I, II, III, IV, V -->
| legal_status      = 
| routes_of_administration = 
}}

'''E-4031''' is an experimental [[Antiarrhythmic agent#Class III agents|class III antiarrhythmic drug ]] that blocks [[potassium channel]]s of the [[HERG|hERG-type]].<ref>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.</ref>

== Chemistry ==
E-4031 is a synthetized [[toxin]] that is a methanesulfonanilide class III antiarrhythmic drug.<ref>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</ref>

== Target ==
E-4031 acts on a specific class of [[voltage-gated potassium channel]]s mainly found in the heart, the hERG channels. hERG channels (Kv11.1) mediate the [[HERG#Biological function|I<sub>Kr</sub>]] current, which repolarizes the myocardial cells.<ref>Gerlach AC, Stoehr SJ, Castle NA (2009 Oct 5. [Epub ahead of print]) Pharmacological Removal of hERG Potassium Channel Inactivation by ICA-105574.</ref><ref>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</ref> The hERG channel is encoded by ether-a-go-go related gene (hERG).<ref name="Weinsberg">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</ref> 

== Mode of action ==
E-4031 blocks hERG-type potassium channels <ref name="Weinsberg"/><ref>Sanguinetti MC, Jurkiewicz NK (1990) Two Components of Cardiac Delayed Rectifier K + Current. ''J Gen Physiol'' '''96''':195-215</ref> by binding to the open channels.<ref name="Spector">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.</ref> 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-terminus|C-terminal]] of the hERG-channel.<ref>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</ref><ref>Mitcheson JS, Chen J, Lin M, Culberson C, and Sanguinetti MC (2000a) A structural basis for drug-induced [[long QT syndrome]]. [[Proceedings of the National Academy of Sciences|''Proc Natl Acad Sci USA'']] '''97''':12329–12333</ref><ref>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</ref><ref>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<sup>+</sup>- channel block. ''J Biol Chem'' '''277''':23587–23595</ref><ref>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</ref><ref name="Perry">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</ref>

Reducing I<sub>Kr</sub> in myocardial cells prolongs the [[cardiac action potential]] and thus prolongs the [[QT interval|QT-interval]].<ref name="Spector"/><ref>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 [[myocyte]]s. ''Cardiovasc Res'' '''26'''(11): 1145-52</ref> In non-cardiac cells, blocking I<sub>kr</sub> has a different effect: it increases the frequency of action potentials.<ref name="Weinsberg"/>

== Toxicity ==
As E-4031 can prolong the QT-interval, it can cause lethal [[Cardiac arrhythmia|arrhythmias]].<ref name="Perry"/>

== 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|QT-interval]].<ref>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</ref>

==References==
{{Reflist}}

{{Potassium channel blockers}}
{{Antiarrhythmic agents}}

[[Category:Potassium channel blockers]]
[[Category:Pyridines]]
[[Category:Piperidines]]
[[Category:Aromatic ketones]]
[[Category:Sulfonamides]]
[[Category:2Fix]]