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Identification
Name Ranolazine
Accession Number DB00243 (APRD01300)
Type small molecule
Groups approved
Description

Ranolazine is an antianginal medication. On January 31, 2006, ranolazine was approved for use in the United States by the FDA for the treatment of chronic angina. [Wikipedia]
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • (-)-Ranolazine
  • ranolazine
  • Ranolazine 2HCl
  • Ranolazine Dihydrochloride
Brand names
  • Ranexa
Brand name mixtures Not Available
Categories
  • Enzyme Inhibitors
CAS number 142387-99-3
Weight Average: 427.5365
Monoisotopic: 427.247106559
Chemical Formula C24H33N3O4
InChI Key InChIKey=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)
Plain Text
IUPAC Name
N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]piperazin-1-yl}acetamide
SMILES
COC1=C(OCC(O)CN2CCN(CC(=O)NC3=C(C)C=CC=C3C)CC2)C=CC=C1
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Acetanilides
Substructures
  • Hydroxy Compounds
  • Phenols and Derivatives
  • Amino Ketones
  • Piperazines
  • Ethers
  • Benzene and Derivatives
  • Acetanilides
  • Carboxylic Acids and Derivatives
  • Aliphatic and Aryl Amines
  • Catechols
  • Heterocyclic compounds
  • Aromatic compounds
  • Anisoles
  • Carboxamides and Derivatives
  • Alcohols and Polyols
  • Phenyl Esters
  • Anilines
Pharmacology
Indication For the treatment of chronic angina. It should be used in combination with amlodipine, beta-blockers or nitrates.
Pharmacodynamics Ranolazine has antianginal and anti-ischemic effects that do not depend upon reductions in heart rate or blood pressure. It is the first new anti-anginal developed in over 20 years.
Mechanism of action The mechanism of action of ranolazine is unknown. It does not increase the rate-pressure product, a measure of myocardial work, at maximal exercise. In vitro studies suggest that ranolazine is a P-gp inhibitor. Ranolazine is believed to have its effects via altering the trans-cellular late sodium current. It is by altering the intracellular sodium level that ranolazine affects the sodium-dependent calcium channels during myocardial ischemia. Thus, ranolazine indirectly prevents the calcium overload that causes cardiac ischemia.
Absorption Absorption is highly variable. After oral administration of ranolazine as a solution, 73% of the dose is systemically available as ranolazine or metabolites. The bioavailability of oral ranolazine relative to that from a solution is 76%.
Volume of distribution Not Available
Protein binding 62%
Metabolism

Hepatic, metabolized mainly by CYP3A and to a lesser extent by CYP2D6. The pharmacologic activity of the metabolites has not been well characterized.
Route of elimination Ranolazine is metabolized rapidly and extensively in the liver and intestine; less than 5% is excreted unchanged in urine and feces.
Half life 7 hours
Clearance Not Available
Toxicity In the event of overdose, the expected symptoms would be dizziness, nausea/vomiting, diplopia, paresthesia, and confusion. Syncope with prolonged loss of consciousness may develop.
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Gilead sciences inc
Packagers
Dosage forms
Form Route Strength
Tablet, film coated, extended release Oral
Prices
Unit description Cost Unit
Ranexa 1000 mg 12 Hour tablet 6.89 USD tablet
Ranexa 1000 mg tablet 6.63 USD tablet
Ranexa 500 mg 12 Hour tablet 4.06 USD tablet
Ranexa 500 mg tablet 4.04 USD tablet
Patents
Country Patent Number Approved Expires
United States 6303607 1999-05-27 2019-05-27
Properties
State solid
Melting point Not Available
Experimental Properties
Property Value Source
water solubility Very slightly soluble PhysProp
logP 1.6 PhysProp
Predicted Properties
Property Value Source
water solubility 1.10e-01 g/l ALOGPS
logP 2.08 ALOGPS
logP 1.53 ChemAxon Molconvert
logS -3.59 ALOGPS
pKa 14.25 ChemAxon Molconvert
hydrogen acceptor count 6 ChemAxon Molconvert
hydrogen donor count 2 ChemAxon Molconvert
polar surface area 74.27 ChemAxon Molconvert
rotatable bond count 9 ChemAxon Molconvert
refractivity 123.46 ChemAxon Molconvert
polarizability 47.22 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference
  1. Hale SL, Kloner RA: Ranolazine, an inhibitor of the late sodium channel current, reduces postischemic myocardial dysfunction in the rabbit. J Cardiovasc Pharmacol Ther. 2006 Dec;11(4):249-55. Pubmed
  2. Fraser H, Belardinelli L, Wang L, Light PE, McVeigh JJ, Clanachan AS: Ranolazine decreases diastolic calcium accumulation caused by ATX-II or ischemia in rat hearts. J Mol Cell Cardiol. 2006 Dec;41(6):1031-8. Epub 2006 Oct 5. Pubmed
  3. Stone PH, Gratsiansky NA, Blokhin A, Huang IZ, Meng L: Antianginal efficacy of ranolazine when added to treatment with amlodipine: the ERICA (Efficacy of Ranolazine in Chronic Angina) trial. J Am Coll Cardiol. 2006 Aug 1;48(3):566-75. Epub 2006 Jun 15. Pubmed
  4. Chaitman BR, Pepine CJ, Parker JO, Skopal J, Chumakova G, Kuch J, Wang W, Skettino SL, Wolff AA: Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina: a randomized controlled trial. JAMA. 2004 Jan 21;291(3):309-16. Pubmed
  5. Morrow DA, Scirica BM, Karwatowska-Prokopczuk E, Murphy SA, Budaj A, Varshavsky S, Wolff AA, Skene A, McCabe CH, Braunwald E: Effects of ranolazine on recurrent cardiovascular events in patients with non-ST-elevation acute coronary syndromes: the MERLIN-TIMI 36 randomized trial. JAMA. 2007 Apr 25;297(16):1775-83. Pubmed
External Links
Resource Link
PubChem Compound 56959 Link_out
PubChem Substance 46505145 Link_out
ChemSpider 51354 Link_out
Therapeutic Targets Database DAP000875 Link_out
Drug Product Database 0 Link_out
RxList http://www.rxlist.com/cgi/generic/ranexa.htm Link_out
Drugs.com http://www.drugs.com/cdi/ranolazine.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Ranolazine Link_out
ATC Codes
  • C01EB18
AHFS Codes Not Available
PDB Entries Not Available
FDA label show (202.8 KB)
MSDS Not Available
Interactions
Drug Interactions Not Available
Food Interactions
  • Grapefruit and grapefruit juice should be avoided throughout treatment.
  • Take without regard to meals.
Targets

1. Sodium channel protein type 5 subunit alpha

Pharmacological action: yes
Actions: inhibitor

This protein 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 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 in the electrocardiogram

Organism class: human
UniProt ID: Q14524 Link_out
Gene: SCN5A Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Hale SL, Kloner RA: Ranolazine, an inhibitor of the late sodium channel current, reduces postischemic myocardial dysfunction in the rabbit. J Cardiovasc Pharmacol Ther. 2006 Dec;11(4):249-55. Pubmed
  2. Rajamani S, Shryock JC, Belardinelli L: Block of tetrodotoxin-sensitive, Na(V)1.7 and tetrodotoxin-resistant, Na(V)1.8, Na+ channels by ranolazine. Channels (Austin). 2008 Nov-Dec;2(6):449-60. Epub 2008 Nov 7. Pubmed

2. Sodium channel protein type 9 subunit alpha

Pharmacological action: unknown
Actions: inhibitor

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 sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient. It is a tetrodotoxin-sensitive Na(+) channel isoform. Plays a role in pain mechanisms, especially in the development of inflammatory pain

Organism class: human
UniProt ID: Q15858 Link_out
Gene: SCN9A Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Rajamani S, Shryock JC, Belardinelli L: Block of tetrodotoxin-sensitive, Na(V)1.7 and tetrodotoxin-resistant, Na(V)1.8, Na+ channels by ranolazine. Channels (Austin). 2008 Nov-Dec;2(6):449-60. Epub 2008 Nov 7. Pubmed
  2. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
Enzymes

1. Cytochrome P450 3A4

Actions: substrate

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 reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4- hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out
Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

2. Cytochrome P450 2D6

Actions: inhibitor

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 antidepressants

UniProt ID: P10635 Link_out
Gene: CYP2D6 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out
Comments
Drug created on June 13, 2005 07:24 / Updated on November 10, 2010 13:37

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.