Identification

Name
Ranolazine
Accession Number
DB00243  (APRD01300)
Type
Small Molecule
Groups
Approved, Investigational
Description

Chronic angina is a common cardiovascular condition affecting millions worldwide and causes significant disability while interfering with daily activities.11 Ranolazine is a well-tolerated piperazine derivative used for the management of this condition, offering relief from uncomfortable and debilitating symptoms.17 With a mechanism of action different from drugs used to treat the same condition, ranolazine is a promising anti-anginal therapy. It was originally approved by the FDA in 2006.15

Structure
Thumb
Synonyms
  • Ranolazina
  • Ranolazine
External IDs
CVT-303 / RS-43285-003
Product Ingredients
IngredientUNIICASInChI Key
Ranolazine hydrochlorideF71253DJUN95635-56-6RJNSNFZXAZXOFX-UHFFFAOYSA-N
Product Images
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
RanexaTablet, film coated, extended release1000 mg/1OralGilead Sciences, Inc.2007-02-12Not applicableUs61958 1004 01 nlmimage10 32431978
RanexaTablet, film coated, extended release500 mg/1OralGilead Sciences, Inc.2006-01-27Not applicableUs61958 100320180907 15195 18u0tsx
RanexaTablet, film coated, extended release500 mg/1OralCardinal Health2007-02-122013-03-31Us61958 1001 01 nlmimage10 e31c7193
RanexaTablet, film coated, extended release500 mg/1OralCardinal Health2006-01-272015-12-31Us61958 1003 01 nlmimage10 a83ed476
RanexaTablet, film coated, extended release500 mg/1OralAphena Pharma Solutions Tennessee, Inc.2006-01-27Not applicableUs
RanexaTablet, film coated, extended release500 mg/1OralCarilion Materials Management2006-01-27Not applicableUs68151 500420180907 15195 f63t8y
RanexaTablet, film coated, extended release1000 mg/1OralGilead Palo Alto, Inc.2007-02-122011-05-31Us
RanexaTablet, film coated, extended release500 mg/1OralGilead Palo Alto, Inc.2006-01-272013-03-31Us
RanexaTablet, film coated, extended release1000 mg/1OralGilead Sciences2007-02-12Not applicableUs
RanexaTablet, film coated, extended release500 mg/1OralGilead Sciences2006-01-27Not applicableUs61958 100120180907 15195 1vtc5i
Additional Data Available
  • Application Number
    Application Number

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  • Product Code
    Product Code

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Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
RanolazineTablet, film coated, extended release500 mg/1OralCipla USA Inc.2019-05-28Not applicableUs
RanolazineTablet, film coated, extended release1000 mg/1OralScieGen Pharmaceuticals, Inc2019-06-04Not applicableUs
RanolazineTablet, film coated, extended release1000 mg/1OralGlenmark Pharmaceuticals Inc., USA2019-07-05Not applicableUs
RanolazineTablet, film coated, extended release500 mg/1OralGlenmark Pharmaceuticals Inc., USA2019-07-05Not applicableUs
RanolazineTablet, film coated, extended release500 mg/1OralScieGen Pharmaceuticals, Inc2019-06-04Not applicableUs
RanolazineTablet, film coated, extended release1000 mg/1OralLupin Pharmaceuticals, Inc.2019-02-27Not applicableUs
RanolazineTablet, extended release1000 mg/1OralViona Pharmaceuticals Inc2019-09-10Not applicableUs
RanolazineTablet, film coated, extended release500 mg/1OralLupin Pharmaceuticals, Inc.2019-02-27Not applicableUs
RanolazineTablet, extended release500 mg/1OralViona Pharmaceuticals Inc2019-09-10Not applicableUs
RanolazineTablet, extended release1000 mg/1OralSun Pharmaceutical Industries, Inc.2019-05-28Not applicableUs
Additional Data Available
  • Application Number
    Application Number

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  • Product Code
    Product Code

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Categories
UNII
A6IEZ5M406
CAS number
95635-55-5
Weight
Average: 427.5365
Monoisotopic: 427.247106559
Chemical Formula
C24H33N3O4
InChI Key
XKLMZUWKNUAPSZ-UHFFFAOYSA-N
InChI
InChI=1S/C24H33N3O4/c1-18-7-6-8-19(2)24(18)25-23(29)16-27-13-11-26(12-14-27)15-20(28)17-31-22-10-5-4-9-21(22)30-3/h4-10,20,28H,11-17H2,1-3H3,(H,25,29)
IUPAC Name
N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]piperazin-1-yl}acetamide
SMILES
COC1=CC=CC=C1OCC(O)CN1CCN(CC(=O)NC2=C(C)C=CC=C2C)CC1

Pharmacology

Indication

Ranolazine is indicated for the treatment of chronic angina. It can be used alone or in conjunction with nitrates, beta-blockers, angiotensin receptor blockers, anti-platelet drugs, calcium channel blockers, lipid-lowering drugs, and ACE inhibitors.17

Ranolazine has also been used off-label for the treatment of certain arrhythmias, including ventricular tachycardia, however, this use is not strongly supported by scientific evidence.3 Ranolazine has also been studied for the treatment of acute coronary syndrome, microvascular coronary dysfunction, arrhythmia, and glycemic control, which are not yet approved indications.1,17

Associated Conditions
Pharmacodynamics

Ranolazine exerts both antianginal and ischemic effects independent from lowering heart rate or blood pressure.9,17 It blocks IKr, the rapid portion of the delayed rectifier potassium current, and prolongs the QTc interval in a dose-dependent fashion. The Ikr is important for cardiac repolarization.17 Ranolazine exerts its therapeutic effects without negative chronotropic, dromotropic, or inotropic actions neither at rest, nor during exercise.1

Mechanism of action

Myocardial ischemia exerts effects on adenosine triphosphate flux, leading to a decrease in the energy available for contraction and relaxation of the heart muscle. Electrolyte balance of sodium and potassium is necessary for maintaining normal cardiac contraction and relaxation. Disruption of adequate sodium and potassium electrolyte balance leads to excessively high concentrations of sodium and calcium, which likely interferes with oxygen supply to the heart muscle. This imbalance eventually leads to angina symptoms of chest pain or pressure, nausea, and dizziness, among others.11,18

The mechanism of action for ranolazine is not fully understood. At therapeutic concentrations, it can inhibit the cardiac late sodium 205 current (INa), which may affect the electrolyte balance in the myocardium, relieving angina symptoms. The clinical significance this inhibition in the treatment of angina symptoms is not yet confirmed.17

Ranolazine inhibits sodium and potassium ion channel currents.1 It has been shown to exert weak activity on L-type calcium channels making it a weak direct vasodilator and exerts minimal direct effects on atrioventricular nodal conduction.2 Some additional mechanisms have been elucidated. Ranolazine exerts antagonistic activity towards the alpha 1 and beta 1 adrenergic receptors and inhibition of fatty acid oxidation.1,12

TargetActionsOrganism
USodium channel protein
inhibitor
Humans
UInward rectifier potassium channel
inhibitor
Humans
UVoltage gated L-type calcium channel
inhibitor
Humans
NAlpha-1 adrenergic receptors
antagonist
Humans
NBeta-1 adrenergic receptor
antagonist
Humans
UFatty acid
other/unknown
Additional Data Available
Adverse Effects

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Contraindications

Structured data covering drug contraindications. Each contraindication describes a scenario in which the drug is not to be used. Includes restrictions on co-administration, contraindicated populations, and more.

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Blackbox Warnings

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Absorption

The time to reach peak serum concentration is quite variable but has been observed to be in the range of 2-6 hours, with steady-state within 3 days.1 The FDA indicates a Tmax of 3-5 hours.17 The average steady-state Cmax is about 2600 ng/mL. Absorption of ranolazine is not significantly affected by food consumption.3 The bioavailability of ranolazine taken in the tablet form compared to that from a solution of ranolazine is about 76%.17

Volume of distribution

The mean apparent volume of distribution of ranolazine is reported to be 53.2 L16 and the average steady-state volume of distribution is estimated to range from 85 to 180 L.6

Protein binding

Approximately 62% of the administered dose of ranolazine is bound to plasma proteins.4,17 Ranolazine appears to have a higher binding affinity for alpha-1 acid glycoprotein.13,16

Metabolism

Ranolazine is rapidly heavily metabolized in the liver an gastrointestinal tract through the activity of the CYP3A4 enzyme with minor contributions from CYP2D6.1,2,17 More than 40 ranolazine metabolites have been found in plasma and more than 100 metabolites have been identified in the urine.4

Ranolazine and some of its metabolites are known to weakly inhibit CYP3A4. However, the activity of the metabolites of ranolazine has not been fully elucidated.16

Route of elimination

From the administered dose, about 3/4 of the dose is excreted renally, while 1/4 of the dose is excreted in the feces. An estimated 5% of an ingested dose is excreted as unchanged drug.1,17

Half life

The apparent terminal half-life of ranolazine is 7 hours.13,17

Clearance

The reported clearance rate of orally administered ranolazine is of 45 L/h when administered at a dose of 500 mg twice daily.6 The clearance rate of ranolazine is dose-dependent and renal impairment can increase ranolazine serum concentration by 40-50%.4

Toxicity

The reported LD50 of oral ranolazine in the rat is 980 mg/kg.MSDS High oral doses of ranolazine have led to dizziness, nausea, and vomiting. These effects have been shown to be dose related. High intravenous doses can cause diplopia, confusion, paresthesia, in addition to syncope. In the case of an overdose, provide supportive therapy accompanied by continuous ECG monitoring for QT interval prolongation.17

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
(R)-warfarinThe serum concentration of (R)-warfarin can be increased when it is combined with Ranolazine.
(S)-WarfarinThe serum concentration of (S)-Warfarin can be increased when it is combined with Ranolazine.
1-(2-Phenylethyl)-4-phenyl-4-acetoxypiperidineThe metabolism of Ranolazine can be decreased when combined with 1-(2-Phenylethyl)-4-phenyl-4-acetoxypiperidine.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Ranolazine.
4-MethoxyamphetamineThe serum concentration of 4-Methoxyamphetamine can be increased when it is combined with Ranolazine.
5-methoxy-N,N-dimethyltryptamineThe serum concentration of 5-methoxy-N,N-dimethyltryptamine can be increased when it is combined with Ranolazine.
9-aminocamptothecinThe metabolism of 9-aminocamptothecin can be decreased when combined with Ranolazine.
AbacavirRanolazine may decrease the excretion rate of Abacavir which could result in a higher serum level.
AbataceptThe metabolism of Ranolazine can be increased when combined with Abatacept.
AbexinostatThe risk or severity of QTc prolongation can be increased when Ranolazine is combined with Abexinostat.
Additional Data Available
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  • Severity
    Severity

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  • Evidence Level
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Food Interactions
  • Avoid grapefruit products.
  • Take with or without food. The absorption is unaffected by food.

References

Synthesis Reference

Gilla Goverdhan, Anumula Raghupathi, Reddy Aalla, Sampath Kurella, Srinivas Vurimidi, Himabindu Ghanta, Mahesh Reddy.(2019).Improved Process for Ranolazine. Organic Process Research & Development 2009, 13, 1, 67-72

US20110151258
General References
  1. Rayner-Hartley E, Sedlak T: Ranolazine: A Contemporary Review. J Am Heart Assoc. 2016 Mar 15;5(3):e003196. doi: 10.1161/JAHA.116.003196. [PubMed:26979079]
  2. Saad M, Mahmoud A, Elgendy IY, Richard Conti C: Ranolazine in Cardiac Arrhythmia. Clin Cardiol. 2016 Mar;39(3):170-8. doi: 10.1002/clc.22476. Epub 2015 Oct 13. [PubMed:26459200]
  3. Reed M, Nicolas D: Ranolazine . [PubMed:29939605]
  4. Mezincescu A, Karthikeyan VJ, Nadar SK: Ranolazine: A true pluripotent cardiovascular drug or jack of all trades, master of none? Sultan Qaboos Univ Med J. 2018 Feb;18(1):e13-e23. doi: 10.18295/squmj.2018.18.01.003. Epub 2018 Apr 4. [PubMed:29666676]
  5. Codolosa JN, Acharjee S, Figueredo VM: Update on ranolazine in the management of angina. Vasc Health Risk Manag. 2014 Jun 24;10:353-62. doi: 10.2147/VHRM.S40477. eCollection 2014. [PubMed:25028555]
  6. Jerling M: Clinical pharmacokinetics of ranolazine. Clin Pharmacokinet. 2006;45(5):469-91. doi: 10.2165/00003088-200645050-00003. [PubMed:16640453]
  7. Thomas D, Karle CA, Kiehn J: The cardiac hERG/IKr potassium channel as pharmacological target: structure, function, regulation, and clinical applications. Curr Pharm Des. 2006;12(18):2271-83. doi: 10.2174/138161206777585102. [PubMed:16787254]
  8. Balestrini S, Sisodiya SM: Pharmacogenomics in epilepsy. Neurosci Lett. 2018 Feb 22;667:27-39. doi: 10.1016/j.neulet.2017.01.014. Epub 2017 Jan 10. [PubMed:28082152]
  9. Gomberg-Maitland M, Schilz R, Mediratta A, Addetia K, Coslet S, Thomeas V, Gillies H, Oudiz RJ: Phase I safety study of ranolazine in pulmonary arterial hypertension. Pulm Circ. 2015 Dec;5(4):691-700. doi: 10.1086/683813. [PubMed:26697176]
  10. Zweiker R, Aichinger J, Metzler B, Lang I, Wallner E, Delle-Karth G: Ranolazine: impact on quality of life in patients with stable angina pectoris, results from an observational study in Austria - the ARETHA AT study. Wien Klin Wochenschr. 2019 Apr;131(7-8):165-173. doi: 10.1007/s00508-019-1481-x. Epub 2019 Apr 8. [PubMed:30963332]
  11. Reddy BM, Weintraub HS, Schwartzbard AZ: Ranolazine: a new approach to treating an old problem. Tex Heart Inst J. 2010;37(6):641-7. [PubMed:21224931]
  12. Bhandari B, Subramanian L: Ranolazine, a partial fatty acid oxidation inhibitor, its potential benefit in angina and other cardiovascular disorders. Recent Pat Cardiovasc Drug Discov. 2007 Jan;2(1):35-9. doi: 10.2174/157489007779606095. [PubMed:18221101]
  13. Chaitman BR: Ranolazine for the treatment of chronic angina and potential use in other cardiovascular conditions. Circulation. 2006 May 23;113(20):2462-72. doi: 10.1161/CIRCULATIONAHA.105.597500. [PubMed:16717165]
  14. FDA approvals [Link]
  15. FDA approvals [Link]
  16. Australian Assessment Report [Link]
  17. Ranolazine FDA Label [Link]
  18. Angina: Mayo clinic [Link]
  19. RANEXA (ranolazine) Australian report [File]
External Links
Human Metabolome Database
HMDB0014388
PubChem Compound
56959
PubChem Substance
46505145
ChemSpider
51354
BindingDB
50173335
RxNav
35829
ChEBI
87690
ChEMBL
CHEMBL1404
Therapeutic Targets Database
DAP000875
PharmGKB
PA164746007
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Ranolazine
ATC Codes
C01EB18 — Ranolazine
FDA label
Download (153 KB)
MSDS
Download (52.8 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedNot AvailableType 2 Diabetes Mellitus2
1CompletedOtherDrug-induced QT Interval Prolongation / Pharmacodynamics / Pharmacokinetics1
1CompletedTreatmentDrug-induced Surface ECG Changes1
1CompletedTreatmentMyotonia Congenita / Myotonia Congenita (Enrollment Complete) / Myotonic Dystrophy 1 / Paramyotonia Congenita1
1CompletedTreatmentPulmonary Arterial Hypertension (PAH)1
1CompletedTreatmentType 2 Diabetes Mellitus1
1RecruitingTreatmentHealthy Male Individuals1
1TerminatedTreatmentSeverely impaired renal function1
2CompletedNot AvailableDiastolic Heart Failure1
2CompletedTreatmentAnginal Pain1
2CompletedTreatmentAtrial Fibrillation (AF)1
2CompletedTreatmentLong qt Syndrome1
2CompletedTreatmentMicrovascular Angina1
2CompletedTreatmentMyocardial Ischemia1
2CompletedTreatmentMyocardial Ischemia / Ventricular Premature Complexes1
2CompletedTreatmentPersistent Atrial Fibrillation1
2CompletedTreatmentType 2 Diabetes Mellitus1
2RecruitingPreventionLong QT Syndrome Type 31
2RecruitingTreatmentAmyotrophic Lateral Sclerosis (ALS)1
2RecruitingTreatmentHCM - Hypertrophic Non-Obstructive Cardiomyopathy1
2TerminatedNot AvailableAtherosclerotic Coronary Vascular Disease1
2TerminatedPreventionAcute Coronary Syndromes (ACS)1
2TerminatedTreatmentAnginal Pain1
2TerminatedTreatmentAtrial Fibrillation (AF) / Heart Failure1
2Unknown StatusTreatmentCongestive Cardiomyopathy1
2, 3CompletedTreatmentAcute Myocardial Ischemia / Coronary Artery Disease1
2, 3TerminatedTreatmentDiarrhoea Predominant Irritable Bowel Syndrome1
2, 3WithdrawnTreatmentAtrial Fibrillation (AF) / Recurrences1
3CompletedNot AvailableAnginal Pain / Coronary Artery Disease / Type 2 Diabetes Mellitus / Type I Diabetes1
3CompletedTreatmentAngina Pectoris / Coronary Artery Disease1
3CompletedTreatmentAnginal Pain1
3CompletedTreatmentAnginal Pain / Pulmonary Arterial Hypertension (PAH)1
3CompletedTreatmentHeart Failure / Ischaemic Cardiomyopathy / Nonischemic Cardiomyopathy1
3CompletedTreatmentMyocardial Ischemia1
3CompletedTreatmentArrhythmia of ventricular origin / Sudden Cardiac Death1
3CompletedTreatmentType 2 Diabetes Mellitus3
3Not Yet RecruitingPreventionCoronary Artery Disease1
3TerminatedTreatmentHeart; Dysfunction Postoperative, Cardiac Surgery1
3Unknown StatusTreatmentAtrial Fibrillation (AF)1
4CompletedNot AvailableChronic Angina1
4CompletedSupportive CareHypertrophic Cardiomyopathy (HCM)1
4CompletedTreatmentAngina Pectoris / Coronary Artery Disease / Type 2 Diabetes Mellitus1
4CompletedTreatmentCardiomyopathy / Chest Pain / Dyspnea1
4CompletedTreatmentCardiovascular Heart Disease / End Stage Renal Disease (ESRD) / End-Stage Renal Disease (ESRD)1
4CompletedTreatmentChronic Stable Angina Pectoris1
4CompletedTreatmentDiastolic Left Ventricular Dysfunction / Pulmonary Hypertension (PH)1
4CompletedTreatmentMetabolic Syndromes / Stable Angina (SA)1
4CompletedTreatmentMicrovascular Angina1
4CompletedTreatmentMyocardial Ischemia / Myocardial Perfusion Imaging1
4CompletedTreatmentPulmonary Hypertension (PH)2
4Not Yet RecruitingPreventionMyocardial Stunning1
4Not Yet RecruitingTreatmentCoronary Artery Disease1
4RecruitingTreatmentAnginal Pain1
4TerminatedTreatmentCoronary Artery Disease / Pain / Peripheral Nervous System Diseases / Polyneuropathies1
4TerminatedTreatmentDiabetic Peripheral Neuropathic Pain (DPN)1
4Unknown StatusDiagnosticCoronary Artery Disease1
4Unknown StatusSupportive CareIschemic Mitral Regurgitation1
4Unknown StatusTreatmentAnginal Pain / Coronary Artery Disease / Metabolic Syndromes1
4Unknown StatusTreatmentAtrial Fibrillation (AF) / Chronic Stable Angina Pectoris / Coronary Artery Disease / Ventricular Tachycardia (VT)1
4Unknown StatusTreatmentIschemic Heart Disease1
4Unknown StatusTreatmentPremature Ventricular Beats1
4WithdrawnTreatmentAngina Pectoris / Coronary Artery Disease / Type 2 Diabetes Mellitus1
4WithdrawnTreatmentAnginal Pain / Peripheral Arterial Disease (PAD)1
4WithdrawnTreatmentArteriosclerosis / Chronic Stable Angina Pectoris / Coronary Artery Disease / Myocardial Ischemia1
Not AvailableCompletedNot AvailableArrhythmia1
Not AvailableCompletedDiagnosticAdenocarcinoma of the Prostate / Bone Metastases / Soft Tissue Metastases / Stage IIA Prostate Cancer / Stage IIB Prostate Cancer / Stage III Prostate Cancer / Stage IV Prostate Cancer1
Not AvailableCompletedPreventionAtrial Fibrillation New Onset / Hemorrhage / Medical Care; Complications, Late Effect of Complications / Prolonged QT Interval / Ventricular Tachycardia (VT)1
Not AvailableCompletedTreatmentAnginal Pain1
Not AvailableCompletedTreatmentHeart Failure With Preserved Ejection Fraction (HFpEF)1
Not AvailableCompletedTreatmentMicrovascular Coronary Dysfunction (MCD)1
Not AvailableCompletedTreatmentPeripheral Arterial Disease (PAD)1
Not AvailableRecruitingTreatmentCoronary Artery Disease / Coronary Microcirculation / Ischaemia / Myocardial Diseases1
Not AvailableTerminatedSupportive CareCardiomyopathy1
Not AvailableTerminatedTreatmentDiastolic Heart Failure / Echocardiography / Ranolazine / Tissue Doppler Ultrasound1
Not AvailableUnknown StatusNot AvailableAnginal Pain / Heart Diseases1
Not AvailableWithdrawnNot AvailableIschaemic Myocardial Dysfunction / Severe Coronary Artery Disease1
Not AvailableWithdrawnOtherSilent Myocardial Ischemia / Type 2 Diabetes Mellitus1

Pharmacoeconomics

Manufacturers
  • Gilead sciences inc
Packagers
  • Atlantic Biologicals Corporation
  • DSM Corp.
  • Gilead Sciences Inc.
Dosage forms
FormRouteStrength
Tablet, film coated, extended releaseOral1000 mg/1
Tablet, film coated, extended releaseOral500 mg/1
Tablet, extended releaseOral1 g/1
Tablet, extended releaseOral1000 mg/1
Tablet, extended releaseOral500 mg/1
Prices
Unit descriptionCostUnit
Ranexa 1000 mg 12 Hour tablet6.89USD tablet
Ranexa 1000 mg tablet6.63USD tablet
Ranexa 500 mg 12 Hour tablet4.06USD tablet
Ranexa 500 mg tablet4.04USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US6303607No2001-10-162019-05-27Us
US6479496No2002-11-122019-05-27Us
US6525057No2003-02-252019-05-27Us
US6562826No2003-05-132019-05-27Us
US6620814No2003-09-162019-05-27Us
US6852724No2005-02-082019-05-27Us
US6864258No2005-03-082019-05-27Us
US6617328No2003-09-092019-05-27Us
US6369062No2002-04-092019-05-27Us
US6503911No2003-01-072019-05-27Us
Additional Data Available
  • Filed On
    Filed On

    The date on which a patent was filed with the relevant government.

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Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)120-124 https://s3-us-west-2.amazonaws.com/drugbank/msds/DB00243.pdf?1550621114
boiling point (°C)624.1 https://pubchem.ncbi.nlm.nih.gov/compound/Ranolazine
water solubility<1 mg/mlMSDS
logP2.07Australian Assessment Report
pKa2.2Australian Assessment Report
Predicted Properties
PropertyValueSource
Water Solubility0.11 mg/mLALOGPS
logP2.08ALOGPS
logP2.83ChemAxon
logS-3.6ALOGPS
pKa (Strongest Acidic)13.6ChemAxon
pKa (Strongest Basic)7.17ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area74.27 Å2ChemAxon
Rotatable Bond Count9ChemAxon
Refractivity123.46 m3·mol-1ChemAxon
Polarizability47.22 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption-0.7425
Blood Brain Barrier-0.5334
Caco-2 permeable-0.5853
P-glycoprotein substrateSubstrate0.8667
P-glycoprotein inhibitor IInhibitor0.7566
P-glycoprotein inhibitor IIInhibitor0.7524
Renal organic cation transporterNon-inhibitor0.7648
CYP450 2C9 substrateNon-substrate0.7965
CYP450 2D6 substrateNon-substrate0.9116
CYP450 3A4 substrateSubstrate0.7456
CYP450 1A2 substrateNon-inhibitor0.9045
CYP450 2C9 inhibitorNon-inhibitor0.907
CYP450 2D6 inhibitorNon-inhibitor0.8287
CYP450 2C19 inhibitorNon-inhibitor0.9025
CYP450 3A4 inhibitorNon-inhibitor0.8309
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.8155
Ames testNon AMES toxic0.8529
CarcinogenicityNon-carcinogens0.9128
BiodegradationNot ready biodegradable0.9936
Rat acute toxicity2.3256 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.8753
hERG inhibition (predictor II)Inhibitor0.8775
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0udi-0010900000-41c6c10d624710416f8e
MS/MS Spectrum - , positiveLC-MS/MSsplash10-004i-1321900000-58e490b47155b2267ecc
MS/MS Spectrum - , positiveLC-MS/MSsplash10-004i-1320900000-9a6cdfcd606e98d38452
MS/MS Spectrum - , positiveLC-MS/MSsplash10-004i-0320900000-ab04122e7d0d6e7c3690
MS/MS Spectrum - , positiveLC-MS/MSsplash10-004i-5951300000-885e790d3cd4d8746c02

Taxonomy

Description
This compound belongs to the class of organic compounds known as anisoles. These are organic compounds containing a methoxybenzene or a derivative thereof.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Phenol ethers
Sub Class
Anisoles
Direct Parent
Anisoles
Alternative Parents
m-Xylenes / Phenoxy compounds / Methoxybenzenes / N-alkylpiperazines / Alkyl aryl ethers / Trialkylamines / Secondary alcohols / 1,2-aminoalcohols / Propargyl-type 1,3-dipolar organic compounds / Carboximidic acids
show 3 more
Substituents
Phenoxy compound / Anisole / M-xylene / Xylene / Methoxybenzene / Alkyl aryl ether / N-alkylpiperazine / Monocyclic benzene moiety / 1,4-diazinane / Piperazine
show 20 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
monocarboxylic acid amide, secondary alcohol, aromatic amide, N-alkylpiperazine, monomethoxybenzene (CHEBI:87690)

Targets

Kind
Protein group
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
Curator comments
Ranolazine administered at normal therapeutic doses can inhibit the cardiac late sodium 205 current (INa), according to the FDA label.
General Function
Voltage-gated sodium channel activity
Specific Function
Mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a...

Components:
References
  1. Rayner-Hartley E, Sedlak T: Ranolazine: A Contemporary Review. J Am Heart Assoc. 2016 Mar 15;5(3):e003196. doi: 10.1161/JAHA.116.003196. [PubMed:26979079]
  2. Saad M, Mahmoud A, Elgendy IY, Richard Conti C: Ranolazine in Cardiac Arrhythmia. Clin Cardiol. 2016 Mar;39(3):170-8. doi: 10.1002/clc.22476. Epub 2015 Oct 13. [PubMed:26459200]
  3. Jerling M: Clinical pharmacokinetics of ranolazine. Clin Pharmacokinet. 2006;45(5):469-91. doi: 10.2165/00003088-200645050-00003. [PubMed:16640453]
  4. Australian Assessment Report [Link]
  5. Ranolazine FDA Label [Link]
Kind
Protein group
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Inward rectifier potassium channel activity
Specific Function
Inward rectifying potassium channel that is activated by phosphatidylinositol 4,5-bisphosphate and that probably participates in controlling the resting membrane potential in electrically excitable...

Components:
References
  1. Saad M, Mahmoud A, Elgendy IY, Richard Conti C: Ranolazine in Cardiac Arrhythmia. Clin Cardiol. 2016 Mar;39(3):170-8. doi: 10.1002/clc.22476. Epub 2015 Oct 13. [PubMed:26459200]
  2. Rayner-Hartley E, Sedlak T: Ranolazine: A Contemporary Review. J Am Heart Assoc. 2016 Mar 15;5(3):e003196. doi: 10.1161/JAHA.116.003196. [PubMed:26979079]
  3. Ranolazine FDA Label [Link]
Kind
Protein group
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Voltage-gated calcium channel activity
Specific Function
Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hor...

Components:
References
  1. Saad M, Mahmoud A, Elgendy IY, Richard Conti C: Ranolazine in Cardiac Arrhythmia. Clin Cardiol. 2016 Mar;39(3):170-8. doi: 10.1002/clc.22476. Epub 2015 Oct 13. [PubMed:26459200]
  2. Peters CH, Sokolov S, Rajamani S, Ruben PC: Effects of the antianginal drug, ranolazine, on the brain sodium channel Na(V)1.2 and its modulation by extracellular protons. Br J Pharmacol. 2013 Jun;169(3):704-16. doi: 10.1111/bph.12150. [PubMed:23472826]
  3. Fredj S, Sampson KJ, Liu H, Kass RS: Molecular basis of ranolazine block of LQT-3 mutant sodium channels: evidence for site of action. Br J Pharmacol. 2006 May;148(1):16-24. doi: 10.1038/sj.bjp.0706709. [PubMed:16520744]
  4. Neshatian L, Strege PR, Rhee PL, Kraichely RE, Mazzone A, Bernard CE, Cima RR, Larson DW, Dozois EJ, Kline CF, Mohler PJ, Beyder A, Farrugia G: Ranolazine inhibits voltage-gated mechanosensitive sodium channels in human colon circular smooth muscle cells. Am J Physiol Gastrointest Liver Physiol. 2015 Sep 15;309(6):G506-12. doi: 10.1152/ajpgi.00051.2015. Epub 2015 Jul 16. [PubMed:26185330]
Kind
Protein group
Organism
Humans
Pharmacological action
No
Actions
Antagonist
Curator comments
Ranolazine has demonstrated α1 adrenergic antagonist action in animal models and human arteries.
General Function
Protein heterodimerization activity
Specific Function
This alpha-adrenergic receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. Its effect is mediated by G(q) and G(11) prot...

Components:
References
  1. Rayner-Hartley E, Sedlak T: Ranolazine: A Contemporary Review. J Am Heart Assoc. 2016 Mar 15;5(3):e003196. doi: 10.1161/JAHA.116.003196. [PubMed:26979079]
  2. Virsolvy A, Farah C, Pertuit N, Kong L, Lacampagne A, Reboul C, Aimond F, Richard S: Antagonism of Nav channels and alpha1-adrenergic receptors contributes to vascular smooth muscle effects of ranolazine. Sci Rep. 2015 Dec 10;5:17969. doi: 10.1038/srep17969. [PubMed:26655634]
  3. Zhao G, Walsh E, Shryock JC, Messina E, Wu Y, Zeng D, Xu X, Ochoa M, Baker SP, Hintze TH, Belardinelli L: Antiadrenergic and hemodynamic effects of ranolazine in conscious dogs. J Cardiovasc Pharmacol. 2011 Jun;57(6):639-47. doi: 10.1097/FJC.0b013e31821458e8. [PubMed:21633249]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Antagonist
Curator comments
Ranolazine has demonstrated B1 antagonist activity in animal models.
General Function
Receptor signaling protein activity
Specific Function
Beta-adrenergic receptors mediate the catecholamine-induced activation of adenylate cyclase through the action of G proteins. This receptor binds epinephrine and norepinephrine with approximately e...
Gene Name
ADRB1
Uniprot ID
P08588
Uniprot Name
Beta-1 adrenergic receptor
Molecular Weight
51322.1 Da
References
  1. Rayner-Hartley E, Sedlak T: Ranolazine: A Contemporary Review. J Am Heart Assoc. 2016 Mar 15;5(3):e003196. doi: 10.1161/JAHA.116.003196. [PubMed:26979079]
  2. Zhao G, Walsh E, Shryock JC, Messina E, Wu Y, Zeng D, Xu X, Ochoa M, Baker SP, Hintze TH, Belardinelli L: Antiadrenergic and hemodynamic effects of ranolazine in conscious dogs. J Cardiovasc Pharmacol. 2011 Jun;57(6):639-47. doi: 10.1097/FJC.0b013e31821458e8. [PubMed:21633249]
  3. Letienne R, Vie B, Puech A, Vieu S, Le Grand B, John GW: Evidence that ranolazine behaves as a weak beta1- and beta2-adrenoceptor antagonist in the rat [correction of cat] cardiovascular system. Naunyn Schmiedebergs Arch Pharmacol. 2001 Apr;363(4):464-71. doi: 10.1007/s002100000378. [PubMed:11330341]
6. Fatty acid
Kind
Group
Organism
Not Available
Pharmacological action
Unknown
Actions
Other/unknown
Curator comments
Ranolazine interrupts the beta-oxidation of fatty acids. The concentration of ranolazine needed to inhibit fatty-acid β-oxidation is at least ten times higher than the therapeutic concentration (<10 µM).
References
  1. Rayner-Hartley E, Sedlak T: Ranolazine: A Contemporary Review. J Am Heart Assoc. 2016 Mar 15;5(3):e003196. doi: 10.1161/JAHA.116.003196. [PubMed:26979079]
  2. Reddy BM, Weintraub HS, Schwartzbard AZ: Ranolazine: a new approach to treating an old problem. Tex Heart Inst J. 2010;37(6):641-7. [PubMed:21224931]
  3. Bhandari B, Subramanian L: Ranolazine, a partial fatty acid oxidation inhibitor, its potential benefit in angina and other cardiovascular disorders. Recent Pat Cardiovasc Drug Discov. 2007 Jan;2(1):35-9. doi: 10.2174/157489007779606095. [PubMed:18221101]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Rayner-Hartley E, Sedlak T: Ranolazine: A Contemporary Review. J Am Heart Assoc. 2016 Mar 15;5(3):e003196. doi: 10.1161/JAHA.116.003196. [PubMed:26979079]
  2. Codolosa JN, Acharjee S, Figueredo VM: Update on ranolazine in the management of angina. Vasc Health Risk Manag. 2014 Jun 24;10:353-62. doi: 10.2147/VHRM.S40477. eCollection 2014. [PubMed:25028555]
  3. Australian Assessment Report [Link]
  4. FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]
  5. Ranolazine FDA Label [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
References
  1. Rayner-Hartley E, Sedlak T: Ranolazine: A Contemporary Review. J Am Heart Assoc. 2016 Mar 15;5(3):e003196. doi: 10.1161/JAHA.116.003196. [PubMed:26979079]
  2. Codolosa JN, Acharjee S, Figueredo VM: Update on ranolazine in the management of angina. Vasc Health Risk Manag. 2014 Jun 24;10:353-62. doi: 10.2147/VHRM.S40477. eCollection 2014. [PubMed:25028555]
  3. Ranolazine FDA Label [Link]

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Binder
General Function
Not Available
Specific Function
Functions as transport protein in the blood stream. Binds various ligands in the interior of its beta-barrel domain. Also binds synthetic drugs and influences their distribution and availability in...
Gene Name
ORM1
Uniprot ID
P02763
Uniprot Name
Alpha-1-acid glycoprotein 1
Molecular Weight
23511.38 Da
References
  1. Chaitman BR: Ranolazine for the treatment of chronic angina and potential use in other cardiovascular conditions. Circulation. 2006 May 23;113(20):2462-72. doi: 10.1161/CIRCULATIONAHA.105.597500. [PubMed:16717165]
  2. Australian Assessment Report [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Transporter activity
Specific Function
Involved in the ATP-dependent secretion of bile salts into the canaliculus of hepatocytes.
Gene Name
ABCB11
Uniprot ID
O95342
Uniprot Name
Bile salt export pump
Molecular Weight
146405.83 Da
References
  1. Pedersen JM, Matsson P, Bergstrom CA, Hoogstraate J, Noren A, LeCluyse EL, Artursson P: Early identification of clinically relevant drug interactions with the human bile salt export pump (BSEP/ABCB11). Toxicol Sci. 2013 Dec;136(2):328-43. doi: 10.1093/toxsci/kft197. Epub 2013 Sep 6. [PubMed:24014644]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. Saad M, Mahmoud A, Elgendy IY, Richard Conti C: Ranolazine in Cardiac Arrhythmia. Clin Cardiol. 2016 Mar;39(3):170-8. doi: 10.1002/clc.22476. Epub 2015 Oct 13. [PubMed:26459200]
  2. Reed M, Nicolas D: Ranolazine . [PubMed:29939605]
  3. Codolosa JN, Acharjee S, Figueredo VM: Update on ranolazine in the management of angina. Vasc Health Risk Manag. 2014 Jun 24;10:353-62. doi: 10.2147/VHRM.S40477. eCollection 2014. [PubMed:25028555]
  4. Montanari F, Ecker GF: Prediction of drug-ABC-transporter interaction--Recent advances and future challenges. Adv Drug Deliv Rev. 2015 Jun 23;86:17-26. doi: 10.1016/j.addr.2015.03.001. Epub 2015 Mar 11. [PubMed:25769815]
  5. Ranolazine FDA Label [Link]
  6. Flockhart Table of Drug Interactions [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Monovalent cation:proton antiporter activity
Specific Function
Solute transporter for tetraethylammonium (TEA), 1-methyl-4-phenylpyridinium (MPP), cimetidine, N-methylnicotinamide (NMN), metformin, creatinine, guanidine, procainamide, topotecan, estrone sulfat...
Gene Name
SLC47A1
Uniprot ID
Q96FL8
Uniprot Name
Multidrug and toxin extrusion protein 1
Molecular Weight
61921.585 Da
References
  1. FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Drug transmembrane transporter activity
Specific Function
Solute transporter for tetraethylammonium (TEA), 1-methyl-4-phenylpyridinium (MPP), cimetidine, N-methylnicotinamide, metformin, creatinine, guanidine, procainamide, topotecan, estrone sulfate, acy...
Gene Name
SLC47A2
Uniprot ID
Q86VL8
Uniprot Name
Multidrug and toxin extrusion protein 2
Molecular Weight
65083.915 Da
References
  1. FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]

Drug created on June 13, 2005 07:24 / Updated on April 02, 2020 01:42

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