Details of the Drug-Related molecule(s) Interaction Atlas

General Information of Drug (ID: DM0L594)

• Drug Name: Ivabradine Drug Info
• Synonyms: Ivabradine; 155974-00-8; Procoralan; Corlanor; Corlentor; UNII-3H48L0LPZQ; S 16257; S-16257; S-16257-2; S 16257-2; 3H48L0LPZQ; CHEMBL471737; CHEBI:85966; C27H36N2O5; 7,8-Dimethoxy-3-(3-(((4,5-dimethoxybenzocyclobutan-1-yl)methyl)methylamino)propyl)-1,3,4,5-tetrahydro-2H-benzazepin-2-one; S-16260-2; s16257; (S)-3-(3-(((3,4-Dimethoxybicyclo(4.2.0)octa-1,3,5-trien-7-yl)methyl)methylamino)propyl)-1,3,4,5-tetrahydro-7,8-dimethoxy-2H-3-benzazepin-2-one; Ivabradine [INN]

Indication

Disease Entry	ICD 11	Status	REF
Angina pectoris	BA40	Approved	[1]
Chronic heart failure	BD1Z	Approved	[2]

• Cross-matching ID:
  PubChem CID: 132999
  ChEBI ID: CHEBI:85966
  CAS Number: CAS 155974-00-8
  TTD Drug ID: DM0L594
  INTEDE Drug ID: DR0897
  ACDINA Drug ID: D00338

Molecule-Related Drug Atlas

Drug(s) Targeting Hyperpolarization cyclic nucleotide-gated channel (HCN)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
SKL-NP	DMRHD6B	Pain	MG30-MG3Z	Phase 2	[7]
ZD-7288	DMPE2B9	Angina pectoris	BA40	Phase 2	[8]
Cilobradine	DM7EAG8	Cardiac arrhythmias	BC9Z	Phase 1	[9]

Drug(s) Metabolized By Cytochrome P450 3A4 (CYP3A4)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Doxorubicin	DMVP5YE	Acute myelogenous leukaemia	2A41	Approved	[10]
Progesterone	DMUY35B	Amenorrhea	GA20.0	Approved	[11]
Tamoxifen	DMLB0EZ	Breast cancer	2C60-2C65	Approved	[12]
Estradiol	DMUNTE3	Acne vulgaris	ED80	Approved	[13]
Acetaminophen	DMUIE76	Allergic rhinitis	CA08.0	Approved	[14]
Imatinib	DM7RJXL	Acute lymphoblastic leukaemia	2A85	Approved	[15]
Etoposide	DMNH3PG	Acute myelogenous leukaemia	2A41	Approved	[16]
Zidovudine	DM4KI7O	Human immunodeficiency virus infection	1C62	Approved	[17]
Prasterone	DM67VKL	Chronic obstructive pulmonary disease	CA22	Approved	[11]
Verapamil	DMA7PEW	Angina pectoris	BA40	Approved	[18]

Drug(s) Affected By Potassium voltage-gated channel subfamily H member 2 (KCNH2)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Metoclopramide	DMFA5MY	Nausea	MD90	Approved	[19]
Quinidine	DMLPICK	N. A.	N. A.	Approved	[20]
Verapamil	DMA7PEW	Angina pectoris	BA40	Approved	[21]
Erythromycin	DM4K7GQ	Acne vulgaris	ED80	Approved	[22]
Clarithromycin	DM4M1SG	Acute maxillary sinusitis		Approved	[22]
Disopyramide	DM5SYZP	Long QT syndrome	BC65.0	Approved	[23]
Propranolol	DM79NTF	Angina pectoris	BA40	Approved	[24]
Amiodarone	DMUTEX3	Tachyarrhythmias	BC71	Approved	[25]
Dofetilide	DMPN1TW	Sinus rhythm disorder	BC9Y	Approved	[26]
Flecainide	DMSQDLE	Tachyarrhythmias	BC71	Approved	[22]

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Hyperpolarization cyclic nucleotide-gated channel (HCN)	TTKLW9S	NOUNIPROTAC	Inhibitor	[3]
Sinus node I(f) channel (SA node IfC)	TTFCQYU	NOUNIPROTAC	Modulator	[4]

Drug-Metabolizing Enzyme (DME)

DME Name	DME ID	UniProt ID	MOA	REF
Cytochrome P450 3A4 (CYP3A4) Main DME	DE4LYSA	CP3A4_HUMAN	Substrate	[5]

Drug Off-Target (DOT)

DOT Name	DOT ID	UniProt ID	Interaction	REF
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Gene/Protein Processing	[6]

References

• [1] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 2357).
• [2] Ivabradine FDA Label
• [3] Antibodies and venom peptides: new modalities for ion channels. Nat Rev Drug Discov. 2019 May;18(5):339-357.
• [4] Ivabradine - the first selective sinus node If channel inhibitor in the treatment of stable angina. Int J Clin Pract. 2006 February; 60(2): 222-228.
• [5] Ivabradine: new drug. Best avoided in stable angina. Prescrire Int. 2007 Apr;16(88):53-6.
• [6] Why are most phospholipidosis inducers also hERG blockers?. Arch Toxicol. 2017 Dec;91(12):3885-3895. doi: 10.1007/s00204-017-1995-9. Epub 2017 May 27.
• [7] A Novel Carbamoyloxy Arylalkanoyl Arylpiperazine Compound (SKL-NP) Inhibits Hyperpolarization-Activated Cyclic Nucleotide-Gated (HCN) Channel Currents in Rat Dorsal Root Ganglion Neurons. Korean J Physiol Pharmacol. 2012 Aug;16(4):237-41.
• [8] ZD 7288, an HCN channel blocker, attenuates chronic visceral pain in irritable bowel syndrome-like rats. World J Gastroenterol. 2014 Feb 28;20(8):2091-7.
• [9] Use-dependent blockade of cardiac pacemaker current (If) by cilobradine and zatebradine. Eur J Pharmacol. 2003 Oct 8;478(2-3):161-71.
• [10] Expression levels and activation of a PXR variant are directly related to drug resistance in osteosarcoma cell lines. Cancer. 2007 Mar 1;109(5):957-65.
• [11] Contribution of human hepatic cytochrome P450 isoforms to regioselective hydroxylation of steroid hormones. Xenobiotica. 1998 Jun;28(6):539-47.
• [12] Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: prominent roles for CYP3A and CYP2D6. J Pharmacol Exp Ther. 2004 Sep;310(3):1062-75.
• [13] Isoform-specific regulation of cytochromes P450 expression by estradiol and progesterone. Drug Metab Dispos. 2013 Feb;41(2):263-9.
• [14] Metabolic interactions between acetaminophen (paracetamol) and two flavonoids, luteolin and quercetin, through in-vitro inhibition studies. J Pharm Pharmacol. 2017 Dec;69(12):1762-1772.
• [15] Potent mechanism-based inhibition of CYP3A4 by imatinib explains its liability to interact with CYP3A4 substrates. Br J Pharmacol. 2012 Apr;165(8):2787-98.
• [16] Effects of morin on the pharmacokinetics of etoposide in rats. Biopharm Drug Dispos. 2007 Apr;28(3):151-6.
• [17] The metabolism of zidovudine by human liver microsomes in vitro: formation of 3'-amino-3'-deoxythymidine. Biochem Pharmacol. 1994 Jul 19;48(2):267-76.
• [18] Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675.
• [19] Comparison of the effects of metoclopramide and domperidone on HERG channels. Pharmacology. 2005 Apr;74(1):31-6. doi: 10.1159/000083234. Epub 2005 Jan 7.
• [20] Further insights into the effect of quinidine in short QT syndrome caused by a mutation in HERG. J Cardiovasc Electrophysiol. 2005 Jan;16(1):54-8. doi: 10.1046/j.1540-8167.2005.04470.x.
• [21] Automated tight seal electrophysiology for assessing the potential hERG liability of pharmaceutical compounds. Assay Drug Dev Technol. 2004 Oct;2(5):497-506. doi: 10.1089/adt.2004.2.497.
• [22] Refining the human iPSC-cardiomyocyte arrhythmic risk assessment model. Toxicol Sci. 2013 Dec;136(2):581-94. doi: 10.1093/toxsci/kft205. Epub 2013 Sep 19.
• [23] Pharmacology of the short QT syndrome N588K-hERG K+ channel mutation: differential impact on selected class I and class III antiarrhythmic drugs. Br J Pharmacol. 2008 Nov;155(6):957-66. doi: 10.1038/bjp.2008.325. Epub 2008 Aug 25.
• [24] Comparison of HERG channel blocking effects of various beta-blockers-- implication for clinical strategy. Br J Pharmacol. 2006 Mar;147(6):642-52. doi: 10.1038/sj.bjp.0706508.
• [25] Inhibitory effects of the class III antiarrhythmic drug amiodarone on cloned HERG potassium channels. Naunyn Schmiedebergs Arch Pharmacol. 1999 Mar;359(3):212-9. doi: 10.1007/pl00005344.
• [26] Redox state dependency of HERGS631C channel pharmacology: relation to C-type inactivation. FEBS Lett. 2000 May 26;474(1):111-5. doi: 10.1016/s0014-5793(00)01586-6.