Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTZOVE0)

• DTT Name: Voltage-gated sodium channel alpha Nav1.5 (SCN5A)
• Synonyms: Voltage-gated sodium channel subunit alpha Nav1.5; Sodium channel protein type V subunit alpha; Sodium channel protein type 5 subunit alpha; Sodium channel protein cardiac muscle subunit alpha; HH1
• Gene Name: SCN5A
• DTT Type: Successful target; [1]
• BioChemical Class: Voltage-gated ion channel
• UniProt ID: SCN5A_HUMAN
• TTD ID: T39716
• Sequence:
  MANFLLPRGTSSFRRFTRESLAAIEKRMAEKQARGSTTLQESREGLPEEEAPRPQLDLQA
  SKKLPDLYGNPPQELIGEPLEDLDPFYSTQKTFIVLNKGKTIFRFSATNALYVLSPFHPI
  RRAAVKILVHSLFNMLIMCTILTNCVFMAQHDPPPWTKYVEYTFTAIYTFESLVKILARG
  FCLHAFTFLRDPWNWLDFSVIIMAYTTEFVDLGNVSALRTFRVLRALKTISVISGLKTIV
  GALIQSVKKLADVMVLTVFCLSVFALIGLQLFMGNLRHKCVRNFTALNGTNGSVEADGLV
  WESLDLYLSDPENYLLKNGTSDVLLCGNSSDAGTCPEGYRCLKAGENPDHGYTSFDSFAW
  AFLALFRLMTQDCWERLYQQTLRSAGKIYMIFFMLVIFLGSFYLVNLILAVVAMAYEEQN
  QATIAETEEKEKRFQEAMEMLKKEHEALTIRGVDTVSRSSLEMSPLAPVNSHERRSKRRK
  RMSSGTEECGEDRLPKSDSEDGPRAMNHLSLTRGLSRTSMKPRSSRGSIFTFRRRDLGSE
  ADFADDENSTAGESESHHTSLLVPWPLRRTSAQGQPSPGTSAPGHALHGKKNSTVDCNGV
  VSLLGAGDPEATSPGSHLLRPVMLEHPPDTTTPSEEPGGPQMLTSQAPCVDGFEEPGARQ
  RALSAVSVLTSALEELEESRHKCPPCWNRLAQRYLIWECCPLWMSIKQGVKLVVMDPFTD
  LTITMCIVLNTLFMALEHYNMTSEFEEMLQVGNLVFTGIFTAEMTFKIIALDPYYYFQQG
  WNIFDSIIVILSLMELGLSRMSNLSVLRSFRLLRVFKLAKSWPTLNTLIKIIGNSVGALG
  NLTLVLAIIVFIFAVVGMQLFGKNYSELRDSDSGLLPRWHMMDFFHAFLIIFRILCGEWI
  ETMWDCMEVSGQSLCLLVFLLVMVIGNLVVLNLFLALLLSSFSADNLTAPDEDREMNNLQ
  LALARIQRGLRFVKRTTWDFCCGLLRQRPQKPAALAAQGQLPSCIATPYSPPPPETEKVP
  PTRKETRFEEGEQPGQGTPGDPEPVCVPIAVAESDTDDQEEDEENSLGTEEESSKQQESQ
  PVSGGPEAPPDSRTWSQVSATASSEAEASASQADWRQQWKAEPQAPGCGETPEDSCSEGS
  TADMTNTAELLEQIPDLGQDVKDPEDCFTEGCVRRCPCCAVDTTQAPGKVWWRLRKTCYH
  IVEHSWFETFIIFMILLSSGALAFEDIYLEERKTIKVLLEYADKMFTYVFVLEMLLKWVA
  YGFKKYFTNAWCWLDFLIVDVSLVSLVANTLGFAEMGPIKSLRTLRALRPLRALSRFEGM
  RVVVNALVGAIPSIMNVLLVCLIFWLIFSIMGVNLFAGKFGRCINQTEGDLPLNYTIVNN
  KSQCESLNLTGELYWTKVKVNFDNVGAGYLALLQVATFKGWMDIMYAAVDSRGYEEQPQW
  EYNLYMYIYFVIFIIFGSFFTLNLFIGVIIDNFNQQKKKLGGQDIFMTEEQKKYYNAMKK
  LGSKKPQKPIPRPLNKYQGFIFDIVTKQAFDVTIMFLICLNMVTMMVETDDQSPEKINIL
  AKINLLFVAIFTGECIVKLAALRHYYFTNSWNIFDFVVVILSIVGTVLSDIIQKYFFSPT
  LFRVIRLARIGRILRLIRGAKGIRTLLFALMMSLPALFNIGLLLFLVMFIYSIFGMANFA
  YVKWEAGIDDMFNFQTFANSMLCLFQITTSAGWDGLLSPILNTGPPYCDPTLPNSNGSRG
  DCGSPAVGILFFTTYIIISFLIVVNMYIAIILENFSVATEESTEPLSEDDFDMFYEIWEK
  FDPEATQFIEYSVLSDFADALSEPLRIAKPNQISLINMDLPMVSGDRIHCMDILFAFTKR
  VLGESGEMDALKIQMEEKFMAANPSKISYEPITTTLRRKHEEVSAMVIQRAFRRHLLQRS
  LKHASFLFRQQAGSGLSEEDAPEREGLIAYVMSENFSRPLGPPSSSSISSTSFPPSYDSV
  TRATSDNLQVRGSDYSHSEDLADFPPSPDRDRESIV
• Function: Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient. It is a tetrodotoxin-resistant Na(+) channel isoform. This channel is responsible for the initial upstroke of the action potential. Channel inactivation is regulated by intracellular calcium levels. This protein mediates the voltage-dependent sodium ion permeability of excitable membranes.
• KEGG Pathway: Adrenergic signaling in cardiomyocytes (hsa04261)
• Reactome Pathway: Interaction between L1 and Ankyrins (R-HSA-445095)

Molecular Interaction Atlas (MIA) of This DTT

14 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Benzonatate	DM9U4FO	Cough	MD12	Approved	[2]
Dibucaine	DMF9G7L	Anaesthesia	9A78.6	Approved	[3]
Disopyramide	DM5SYZP	Long QT syndrome	BC65.0	Approved	[4]
Dyclonine	DMU6OFP	Pain	MG30-MG3Z	Approved	[5]
Ethotoin	DMXWOCP	Complex partial seizure	8A68.0	Approved	[2]
Fosphenytoin	DMOX3LB	Epilepsy	8A60-8A68	Approved	[6]
Hexylcaine	DMEADRK	Anaesthesia	9A78.6	Approved	[2]
Indecainide	DMUV8OR	Dysrhythmias	BC9Z	Approved	[1]
LOMERIZINE	DME0TC8	Migraine	8A80	Approved	[7]
Mephenytoin	DM5UGDK	Epilepsy	8A60-8A68	Approved	[6]
Mexiletine	DMCTE9R	Ventricular tachycardia	BC71	Approved	[4]
Moricizine	DMOMBJW	Arrhythmia	BC9Z	Approved	[8]
Prilocaine	DMI7DZ2	Pain	MG30-MG3Z	Approved	[5]
Tetrodotoxin	DMWMPRG	Bacterial infection	1A00-1C4Z	Approved	[3]

1 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
F-15845	DMAH12E	Angina pectoris	BA40	Phase 1	[9]

4 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Aryl carboxamide derivative 1	DMTZRCW	N. A.	N. A.	Patented	[10]
Aryl carboxamide derivative 2	DM146TA	N. A.	N. A.	Patented	[10]
Aryl carboxamide derivative 3	DM6FQ8L	N. A.	N. A.	Patented	[10]
Dihydrobenzoxazine and tetrahydroquinoxaline sulfonamide derivative 1	DMUNFAT	N. A.	N. A.	Patented	[10]

5 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Encainide	DMK0GHV	Heart arrhythmia	BC65	Withdrawn from market	[8]
LUBELUZOLE	DMFGMD9	Neurological disorder	6B60	Discontinued in Preregistration	[7]
Acecainide	DMKM543	Solid tumour/cancer	2A00-2F9Z	Discontinued in Phase 3	[5]
SIPATRIGINE	DMMQ4GC	Neurological disorder	6B60	Discontinued in Phase 2	[7]
PD-85639	DMNUKB4	N. A.	N. A.	Terminated	[7]

7 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
1-[5-(4-Chlorophenyl)-2-furoyl]piperazine	DM8NMAV	Discovery agent	N.A.	Investigative	[11]
aconitine	DMFOZ60	Discovery agent	N.A.	Investigative	[12]
batrachotoxin	DMYH9SU	Discovery agent	N.A.	Investigative	[13]
KC-12291	DMY6QOR	Discovery agent	N.A.	Investigative	[14]
N-(4-Methyl-benzoyl)-N'-phenethyl-guanidine	DMCZD37	Discovery agent	N.A.	Investigative	[15]
N-Butyl-N'-(4-methyl-benzoyl)-guanidine	DM8U70E	Discovery agent	N.A.	Investigative	[15]
veratridine	DMUF8JZ	Discovery agent	N.A.	Investigative	[16]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Asthma	CA23	Nasal and bronchial airway	8.56E-05	-0.25	-0.53

References

• [1] Electrophysiological studies of indecainide hydrochloride, a new antiarrhythmic agent, in canine cardiac tissues. J Cardiovasc Pharmacol. 1984 Jul-Aug;6(4):614-21.
• [2] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [3] Halothane attenuates the cerebroprotective action of several Na+ and Ca2+ channel blockers via reversal of their ion channel blockade. Eur J Pharmacol. 2002 Oct 4;452(2):175-81.
• [4] Effect of sodium channel blockers on ST segment, QRS duration, and corrected QT interval in patients with Brugada syndrome. J Cardiovasc Electrophysiol. 2000 Dec;11(12):1320-9.
• [5] Monoamine transporter and sodium channel mechanisms in the rapid pressor response to cocaine. Pharmacol Biochem Behav. 1998 Feb;59(2):305-12.
• [6] Lacosamide: a new approach to target voltage-gated sodium currents in epileptic disorders. CNS Drugs. 2009;23(7):555-68.
• [7] Medicinal chemistry of neuronal voltage-gated sodium channel blockers. J Med Chem. 2001 Jan 18;44(2):115-37.
• [8] From first class to third class: recent upheaval in antiarrhythmic therapy--lessons from clinical trials. Am J Cardiol. 1996 Aug 29;78(4A):28-33.
• [9] Selective inhibition of persistent sodium current by F 15845 prevents ischaemia-induced arrhythmias. Br J Pharmacol. 2010 Sep;161(1):79-91.
• [10] Sodium channel blockers: a patent review (2010 - 2014).Expert Opin Ther Pat. 2015 Mar;25(3):279-90.
• [11] Discovery of potent furan piperazine sodium channel blockers for treatment of neuropathic pain. Bioorg Med Chem. 2008 Jun 15;16(12):6379-86.
• [12] Properties of aconitine-modified sodium channels in single cells of mouse ventricular myocardium. Gen Physiol Biophys. 1986 Oct;5(5):473-84.
• [13] Binding of [3H]batrachotoxinin A benzoate to specific sites on rat cardiac sodium channels. Mol Pharmacol. 1986 Dec;30(6):617-23.
• [14] Sodium late current blockers in ischemia reperfusion: is the bullet magic J Med Chem. 2008 Jul 10;51(13):3856-66.
• [15] Solution-phase, parallel synthesis and pharmacological evaluation of acylguanidine derivatives as potential sodium channel blockers. Bioorg Med Chem Lett. 2001 Dec 17;11(24):3151-5.
• [16] Sodium channel comodification with full activator reveals veratridine reaction dynamics. Mol Pharmacol. 1990 Feb;37(2):144-8.