title: A novel, potent, and selective inhibitor of cardiac late sodium current suppresses experimental arrhythmias.
abstract: Inhibition of cardiac late sodium current (late I(Na)) is a strategy to suppress arrhythmias and sodium-dependent calcium overload associated with myocardial ischemia and heart failure. Current inhibitors of late I(Na) are unselective and can be proarrhythmic. This study introduces GS967 (6-[4-(trifluoromethoxy)phenyl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine), a potent and selective inhibitor of late I(Na), and demonstrates its effectiveness to suppress ventricular arrhythmias. The effects of GS967 on rabbit ventricular myocyte ion channel currents and action potentials were determined. Anti-arrhythmic actions of GS967 were characterized in ex vivo and in vivo rabbit models of reduced repolarization reserve and ischemia. GS967 inhibited Anemonia sulcata toxin II (ATX-II)-induced late I(Na) in ventricular myocytes and isolated hearts with IC(50) values of 0.13 and 0.21 µM, respectively. Reduction of peak I(Na) by GS967 was minimal at a holding potential of -120 mV but increased at -80 mV. GS967 did not prolong action potential duration or the QRS interval. GS967 prevented and reversed proarrhythmic effects (afterdepolarizations and torsades de pointes) of the late I(Na) enhancer ATX-II and the I(Kr) inhibitor E-4031 in isolated ventricular myocytes and hearts. GS967 significantly attenuated the proarrhythmic effects of methoxamine+clofilium and suppressed ischemia-induced arrhythmias. GS967 was more potent and effective to reduce late I(Na) and arrhythmias than either flecainide or ranolazine. Results of all studies and assays of binding and activity of GS967 at numerous receptors, transporters, and enzymes indicated that GS967 selectively inhibited late I(Na). In summary, GS967 selectively suppressed late I(Na) and prevented and/or reduced the incidence of experimentally induced arrhythmias in rabbit myocytes and hearts.
authors.affiliation: Department of Biology, MD Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA. luiz.belardinelli@gilead.com
authors.forename: Luiz
authors.initials: L
authors.lastname: Belardinelli
authors.forename: Gongxin
authors.initials: G
authors.lastname: Liu
authors.forename: Cathy
authors.initials: C
authors.lastname: Smith-Maxwell
authors.forename: Wei-Qun
authors.initials: WQ
authors.lastname: Wang
authors.forename: Nesrine
authors.initials: N
authors.lastname: El-Bizri
authors.forename: Ryoko
authors.initials: R
authors.lastname: Hirakawa
authors.forename: Serge
authors.initials: S
authors.lastname: Karpinski
authors.forename: Cindy Hong
authors.initials: CH
authors.lastname: Li
authors.forename: Lufei
authors.initials: L
authors.lastname: Hu
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Li
authors.forename: William
authors.initials: W
authors.lastname: Crumb
authors.forename: Lin
authors.initials: L
authors.lastname: Wu
authors.forename: Dmitry
authors.initials: D
authors.lastname: Koltun
authors.forename: Jeff
authors.initials: J
authors.lastname: Zablocki
authors.forename: Lina
authors.initials: L
authors.lastname: Yao
authors.forename: Arvinder K
authors.initials: AK
authors.lastname: Dhalla
authors.forename: Sridharan
authors.initials: S
authors.lastname: Rajamani
authors.forename: John C
authors.initials: JC
authors.lastname: Shryock
mesh_terms: D000083:Acetanilides / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003064:Cnidarian Venoms / Q000494:pharmacology; D005260:Female; D005424:Flecainide / Q000494:pharmacology; D006329:Heart Conduction System / Q000187:drug effects; D008133:Long QT Syndrome / Q000235:genetics / Q000503:physiopathology; D009154:Mutation / Q000502:physiology; D017202:Myocardial Ischemia / Q000150:complications / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010879:Piperazines / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D011817:Rabbits; D000069458:Ranolazine; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D014230:Triazoles / Q000494:pharmacology*
chemical_list: C578456:6-(4-(trifluoromethoxy)phenyl)-3-(trifluoromethyl)(1,2,4)triazolo(4,3-a)pyridine; D000083:Acetanilides; D000889:Anti-Arrhythmia Agents; D002316:Cardiotonic Agents; D003064:Cnidarian Venoms; D010879:Piperazines; D026902:Potassium Channel Blockers; D011725:Pyridines; D000644:Quaternary Ammonium Compounds; D026941:Sodium Channel Blockers; D014230:Triazoles; C028800:toxin II (Anemonia sulcata); C022799:clofilium; D000069458:Ranolazine; D005424:Flecainide