U.S. Department of Health & Human Services Divider Arrow National Institutes of Health Divider Arrow NCATS

Details

Stereochemistry RACEMIC
Molecular Formula C24H33N3O4
Molecular Weight 427.5374
Optical Activity ( + / - )
Defined Stereocenters 0 / 1
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of RANOLAZINE

SMILES

Cc1cccc(C)c1N=C(CN2CCN(CC2)CC(COc3ccccc3OC)O)O

InChI

InChIKey=XKLMZUWKNUAPSZ-UHFFFAOYSA-N
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)

HIDE SMILES / InChI

Molecular Formula C24H33N3O4
Molecular Weight 427.5374
Charge 0
Count
Stereochemistry RACEMIC
Additional Stereochemistry No
Defined Stereocenters 0 / 1
E/Z Centers 0
Optical Activity ( + / - )

Description
Curator's Comment:: description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/16196483

Ranolazine is a metabolic modulator developed by Syntex (Roche) and sold under the trade name Ranexa by Gilead Sciences. Ranexa has antianginal and anti-ischemic effects that do not depend upon reductions in heart rate or blood pressure. 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. Because Ranexa prolongs the QT interval, it should be reserved for patients who have not achieved an adequate response with other antianginal drugs. Ranexa should be used in combination with amlodipine, beta-blockers or nitrates. The effect on angina rate or exercise tolerance appeared to be smaller in women than men.

CNS Activity

Curator's Comment:: Known to be CNS active in rats. Human data not available

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
RANEXA

Approved Use

Ranexa is indicated for the treatment of chronic angina. Ranexa may be used with beta-blockers, nitrates, calcium channel blockers, anti-platelet therapy, lipid-lowering therapy, ACE inhibitors, and angiotensin receptor blockers. Ranexa is indicated for the treatment of chronic angina. (1)

Launch Date

1.13831995E12
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
741.5 ng/mL
500 mg single, oral
dose: 500 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
RANOLAZINE plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FASTED
2600 ng/mL
1000 mg 2 times / day steady-state, oral
dose: 1000 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
RANOLAZINE plasma
Homo sapiens
population: UNKNOWN
age: UNKNOWN
sex: UNKNOWN
food status: UNKNOWN
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
9862.7 ng × h/mL
500 mg single, oral
dose: 500 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
RANOLAZINE plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FASTED
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
6.4 h
500 mg single, oral
dose: 500 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
RANOLAZINE plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FASTED
7 h
1000 mg 2 times / day steady-state, oral
dose: 1000 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
RANOLAZINE plasma
Homo sapiens
population: UNKNOWN
age: UNKNOWN
sex: UNKNOWN
food status: UNKNOWN
Funbound

Funbound

ValueDoseCo-administeredAnalytePopulation
38%
1000 mg 2 times / day steady-state, oral
dose: 1000 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
RANOLAZINE plasma
Homo sapiens
population: UNKNOWN
age: UNKNOWN
sex: UNKNOWN
food status: UNKNOWN
Doses

Doses

DosePopulationAdverse events​
2000 mg single, oral
Highest studied dose
Dose: 2000 mg
Route: oral
Route: single
Dose: 2000 mg
Sources:
unhealthy, 57-83 years
n = 18
Health Status: unhealthy
Condition: Atrial fibrillation
Age Group: 57-83 years
Sex: M+F
Population Size: 18
Sources:
1500 mg 2 times / day steady, oral
Highest studied dose
Dose: 1500 mg, 2 times / day
Route: oral
Route: steady
Dose: 1500 mg, 2 times / day
Sources:
unhealthy, 64.3 years (range: 39–85 years)
n = 60
Health Status: unhealthy
Condition: Stable Angina
Age Group: 64.3 years (range: 39–85 years)
Sex: M+F
Population Size: 60
Sources:
Other AEs: Dizziness, Nausea...
Other AEs:
Dizziness (12.3%)
Nausea (8.6%)
Asthenia (6.4%)
Constipation (4.3%)
Angina pectoris (3.2%)
Headache (2.7%)
Sweating (2.7%)
Sources:
50 g single, oral
Overdose
Dose: 50 g
Route: oral
Route: single
Dose: 50 g
Co-administed with::
quetiapine(therapeutic or subtherapeutic)
valproate(therapeutic or subtherapeutic)
mirtazapine(therapeutic or subtherapeutic)
Sources:
unhealthy, 65 years
n = 1
Health Status: unhealthy
Age Group: 65 years
Sex: F
Population Size: 1
Sources:
Other AEs: Electrocardiogram QTc interval prolonged...
Other AEs:
Electrocardiogram QTc interval prolonged (grade 5)
Sources:
1000 mg 2 times / day steady, oral
Recommended
Dose: 1000 mg, 2 times / day
Route: oral
Route: steady
Dose: 1000 mg, 2 times / day
Sources:
unhealthy, adult
n = 835
Health Status: unhealthy
Condition: chronic angina
Age Group: adult
Population Size: 835
Sources:
Disc. AE: Dizziness, Nausea...
AEs leading to
discontinuation/dose reduction:
Dizziness (1.3%)
Nausea (1%)
Asthenia (0.5%)
Constipation (0.5%)
Headache (0.5%)
Sources:
AEs

AEs

AESignificanceDosePopulation
Dizziness 12.3%
1500 mg 2 times / day steady, oral
Highest studied dose
Dose: 1500 mg, 2 times / day
Route: oral
Route: steady
Dose: 1500 mg, 2 times / day
Sources:
unhealthy, 64.3 years (range: 39–85 years)
n = 60
Health Status: unhealthy
Condition: Stable Angina
Age Group: 64.3 years (range: 39–85 years)
Sex: M+F
Population Size: 60
Sources:
Headache 2.7%
1500 mg 2 times / day steady, oral
Highest studied dose
Dose: 1500 mg, 2 times / day
Route: oral
Route: steady
Dose: 1500 mg, 2 times / day
Sources:
unhealthy, 64.3 years (range: 39–85 years)
n = 60
Health Status: unhealthy
Condition: Stable Angina
Age Group: 64.3 years (range: 39–85 years)
Sex: M+F
Population Size: 60
Sources:
Sweating 2.7%
1500 mg 2 times / day steady, oral
Highest studied dose
Dose: 1500 mg, 2 times / day
Route: oral
Route: steady
Dose: 1500 mg, 2 times / day
Sources:
unhealthy, 64.3 years (range: 39–85 years)
n = 60
Health Status: unhealthy
Condition: Stable Angina
Age Group: 64.3 years (range: 39–85 years)
Sex: M+F
Population Size: 60
Sources:
Angina pectoris 3.2%
1500 mg 2 times / day steady, oral
Highest studied dose
Dose: 1500 mg, 2 times / day
Route: oral
Route: steady
Dose: 1500 mg, 2 times / day
Sources:
unhealthy, 64.3 years (range: 39–85 years)
n = 60
Health Status: unhealthy
Condition: Stable Angina
Age Group: 64.3 years (range: 39–85 years)
Sex: M+F
Population Size: 60
Sources:
Constipation 4.3%
1500 mg 2 times / day steady, oral
Highest studied dose
Dose: 1500 mg, 2 times / day
Route: oral
Route: steady
Dose: 1500 mg, 2 times / day
Sources:
unhealthy, 64.3 years (range: 39–85 years)
n = 60
Health Status: unhealthy
Condition: Stable Angina
Age Group: 64.3 years (range: 39–85 years)
Sex: M+F
Population Size: 60
Sources:
Asthenia 6.4%
1500 mg 2 times / day steady, oral
Highest studied dose
Dose: 1500 mg, 2 times / day
Route: oral
Route: steady
Dose: 1500 mg, 2 times / day
Sources:
unhealthy, 64.3 years (range: 39–85 years)
n = 60
Health Status: unhealthy
Condition: Stable Angina
Age Group: 64.3 years (range: 39–85 years)
Sex: M+F
Population Size: 60
Sources:
Nausea 8.6%
1500 mg 2 times / day steady, oral
Highest studied dose
Dose: 1500 mg, 2 times / day
Route: oral
Route: steady
Dose: 1500 mg, 2 times / day
Sources:
unhealthy, 64.3 years (range: 39–85 years)
n = 60
Health Status: unhealthy
Condition: Stable Angina
Age Group: 64.3 years (range: 39–85 years)
Sex: M+F
Population Size: 60
Sources:
Electrocardiogram QTc interval prolonged grade 5
50 g single, oral
Overdose
Dose: 50 g
Route: oral
Route: single
Dose: 50 g
Co-administed with::
quetiapine(therapeutic or subtherapeutic)
valproate(therapeutic or subtherapeutic)
mirtazapine(therapeutic or subtherapeutic)
Sources:
unhealthy, 65 years
n = 1
Health Status: unhealthy
Age Group: 65 years
Sex: F
Population Size: 1
Sources:
Asthenia 0.5%
Disc. AE
1000 mg 2 times / day steady, oral
Recommended
Dose: 1000 mg, 2 times / day
Route: oral
Route: steady
Dose: 1000 mg, 2 times / day
Sources:
unhealthy, adult
n = 835
Health Status: unhealthy
Condition: chronic angina
Age Group: adult
Population Size: 835
Sources:
Constipation 0.5%
Disc. AE
1000 mg 2 times / day steady, oral
Recommended
Dose: 1000 mg, 2 times / day
Route: oral
Route: steady
Dose: 1000 mg, 2 times / day
Sources:
unhealthy, adult
n = 835
Health Status: unhealthy
Condition: chronic angina
Age Group: adult
Population Size: 835
Sources:
Headache 0.5%
Disc. AE
1000 mg 2 times / day steady, oral
Recommended
Dose: 1000 mg, 2 times / day
Route: oral
Route: steady
Dose: 1000 mg, 2 times / day
Sources:
unhealthy, adult
n = 835
Health Status: unhealthy
Condition: chronic angina
Age Group: adult
Population Size: 835
Sources:
Nausea 1%
Disc. AE
1000 mg 2 times / day steady, oral
Recommended
Dose: 1000 mg, 2 times / day
Route: oral
Route: steady
Dose: 1000 mg, 2 times / day
Sources:
unhealthy, adult
n = 835
Health Status: unhealthy
Condition: chronic angina
Age Group: adult
Population Size: 835
Sources:
Dizziness 1.3%
Disc. AE
1000 mg 2 times / day steady, oral
Recommended
Dose: 1000 mg, 2 times / day
Route: oral
Route: steady
Dose: 1000 mg, 2 times / day
Sources:
unhealthy, adult
n = 835
Health Status: unhealthy
Condition: chronic angina
Age Group: adult
Population Size: 835
Sources:
Overview

OverviewOther

Other InhibitorOther SubstrateOther Inducer




Drug as perpetrator​

Drug as perpetrator​

TargetModalityActivityMetaboliteClinical evidence
moderate
no
yes [Ki 197 uM]
yes (co-administration study)
Comment: ketoconazole, diltiazem and verapamil increase the exposure to ranolazine by a factor of 2.0 or more and the impact on the PK of ranolazine is clinically significant
Page: 97, 145
yes
yes
Drug as victim

Drug as victim

TargetModalityActivityMetaboliteClinical evidence
major
yes (co-administration study)
Comment: ketoconazole, diltiazem and verapamil increase the exposure to ranolazine by a factor of 2.0 or more and the impact on the PK of ranolazine is clinically significant
Page: 96, 131
minor
yes (co-administration study)
Comment: paroxetine increased the exposure of ranolazine by <20%
Page: 96, 131
yes
Tox targets

Tox targets

TargetModalityActivityMetaboliteClinical evidence
Sourcing

Sourcing

Vendor/AggregatorIDURL
PubMed

PubMed

TitleDatePubMed
Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina: a randomized controlled trial.
2004 Jan 21
Ranolazine, an inhibitor of the late sodium channel current, reduces postischemic myocardial dysfunction in the rabbit.
2006 Dec
Effects of ranolazine on recurrent cardiovascular events in patients with non-ST-elevation acute coronary syndromes: the MERLIN-TIMI 36 randomized trial.
2007 Apr 25
Ranolazine block of human Na v 1.4 sodium channels and paramyotonia congenita mutants.
2011 Mar-Apr
Patents

Sample Use Guides

Dosing should be initiated at 500 mg b.i.d. and increased to 1000 mg b.i.d., as needed, based on clinical symptoms. The maximum recommended daily dose is 1000 mg b.i.d.
Route of Administration: Oral
Ranolazine (Rn) acts in the central nervous system and it has been proposed for the treatment of pain and epileptic disorders. Under the hypothesis that ranolazine could act as a neuroprotective drug, was studied its effects on astrocytes and neurons in primary culture. It was incubated rat astrocytes and neurons in primary cultures for 24 hours with Rn (10-7, 10-6 and 10-5 M). Cell viability and proliferation were measured using trypan blue exclusion assay, MTT conversion assay and LDH release assay. Apoptosis was determined by Caspase 3 activity assay. The effects of Rn on pro-inflammatory mediators IL-β and TNF-α was determined by ELISA technique, and protein expression levels of Smac/Diablo, PPAR-γ, Mn-SOD and Cu/Zn-SOD by western blot technique. Rn could act as a neuroprotective drug in the central nervous system by promoting astrocyte viability, preventing necrosis and apoptosis, inhibiting inflammatory phenomena and inducing anti-inflammatory and antioxidant agents.
Substance Class Chemical
Created
by admin
on Fri Jun 25 21:34:45 UTC 2021
Edited
by admin
on Fri Jun 25 21:34:45 UTC 2021
Record UNII
A6IEZ5M406
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
RANOLAZINE
EMA EPAR   INN   MART.   MI   ORANGE BOOK   USAN   USP-RS   VANDF   WHO-DD  
INN   USAN  
Official Name English
RANOLAZINE [USP-RS]
Common Name English
CVT-303
Code English
RAN D
Common Name English
RAN4
Common Name English
RANEXA
Brand Name English
(+/-)-N-(2,6-DIMETHYLPHENYL)-4-(2-HYDROXY-3-(2-METHOXYPHENOXY)PROPYL)-1-PIPERAZINEACETAMIDE
Systematic Name English
1-PIPERAZINEACETAMIDE, N-(2,6-DIMETHYLPHENYL)-4-(2-HYDROXY-3-(2-METHOXYPHENOXY)PROPYL)-, (+/-)
Common Name English
RANOLAZINE [WHO-DD]
Common Name English
RANOLAZINE [EMA EPAR]
Common Name English
NSC-759100
Code English
N-(2,6-DIMETHYLPHENYL)-2-(4-((2RS)-2-HYDROXY-3-(2-METHOXYPHENOXY)PROPYL)PIPERAZIN-1-YL)ACETAMIDE
Systematic Name English
1-PIPERAZINEACETAMIDE, N-(2,6-DIMETHYLPHENYL)-4-(2-HYDROXY-3-(2-METHOXYPHENOXY)PROPYL)-
Systematic Name English
RS-43285-003
Code English
RANOLAZINE [VANDF]
Common Name English
RANOLAZINE [USAN]
Common Name English
RANOLAZINE [ORANGE BOOK]
Common Name English
RANOLAZINE [INN]
Common Name English
RANOLAZINE [MART.]
Common Name English
RANOLAZINE [MI]
Common Name English
Classification Tree Code System Code
LIVERTOX 834
Created by admin on Fri Jun 25 21:34:45 UTC 2021 , Edited by admin on Fri Jun 25 21:34:45 UTC 2021
WHO-VATC QC01EB18
Created by admin on Fri Jun 25 21:34:45 UTC 2021 , Edited by admin on Fri Jun 25 21:34:45 UTC 2021
EMA ASSESSMENT REPORTS RANEXA (AUTHORIZED: ANGINA PECTORIS)
Created by admin on Fri Jun 25 21:34:45 UTC 2021 , Edited by admin on Fri Jun 25 21:34:45 UTC 2021
NDF-RT N0000175427
Created by admin on Fri Jun 25 21:34:45 UTC 2021 , Edited by admin on Fri Jun 25 21:34:45 UTC 2021
WHO-ATC C01EB18
Created by admin on Fri Jun 25 21:34:45 UTC 2021 , Edited by admin on Fri Jun 25 21:34:45 UTC 2021
NCI_THESAURUS C93038
Created by admin on Fri Jun 25 21:34:45 UTC 2021 , Edited by admin on Fri Jun 25 21:34:45 UTC 2021
NCI_THESAURUS C78322
Created by admin on Fri Jun 25 21:34:45 UTC 2021 , Edited by admin on Fri Jun 25 21:34:45 UTC 2021
Code System Code Type Description
ChEMBL
CHEMBL1404
Created by admin on Fri Jun 25 21:34:45 UTC 2021 , Edited by admin on Fri Jun 25 21:34:45 UTC 2021
PRIMARY
USP_CATALOG
1598744
Created by admin on Fri Jun 25 21:34:45 UTC 2021 , Edited by admin on Fri Jun 25 21:34:45 UTC 2021
PRIMARY USP-RS
RXCUI
35829
Created by admin on Fri Jun 25 21:34:45 UTC 2021 , Edited by admin on Fri Jun 25 21:34:45 UTC 2021
PRIMARY RxNorm
CAS
95635-55-5
Created by admin on Fri Jun 25 21:34:45 UTC 2021 , Edited by admin on Fri Jun 25 21:34:45 UTC 2021
PRIMARY
FDA UNII
A6IEZ5M406
Created by admin on Fri Jun 25 21:34:45 UTC 2021 , Edited by admin on Fri Jun 25 21:34:45 UTC 2021
PRIMARY
PUBCHEM
56959
Created by admin on Fri Jun 25 21:34:45 UTC 2021 , Edited by admin on Fri Jun 25 21:34:45 UTC 2021
PRIMARY
INN
5946
Created by admin on Fri Jun 25 21:34:45 UTC 2021 , Edited by admin on Fri Jun 25 21:34:45 UTC 2021
PRIMARY
DRUG CENTRAL
2359
Created by admin on Fri Jun 25 21:34:45 UTC 2021 , Edited by admin on Fri Jun 25 21:34:45 UTC 2021
PRIMARY
EVMPD
SUB10259MIG
Created by admin on Fri Jun 25 21:34:45 UTC 2021 , Edited by admin on Fri Jun 25 21:34:45 UTC 2021
PRIMARY
NDF-RT
N0000182137
Created by admin on Fri Jun 25 21:34:45 UTC 2021 , Edited by admin on Fri Jun 25 21:34:45 UTC 2021
PRIMARY Cytochrome P450 2D6 Inhibitors [MoA]
MERCK INDEX
M9499
Created by admin on Fri Jun 25 21:34:45 UTC 2021 , Edited by admin on Fri Jun 25 21:34:45 UTC 2021
PRIMARY Merck Index
IUPHAR
7291
Created by admin on Fri Jun 25 21:34:45 UTC 2021 , Edited by admin on Fri Jun 25 21:34:45 UTC 2021
PRIMARY
HSDB
7924
Created by admin on Fri Jun 25 21:34:45 UTC 2021 , Edited by admin on Fri Jun 25 21:34:45 UTC 2021
PRIMARY
MESH
C055512
Created by admin on Fri Jun 25 21:34:45 UTC 2021 , Edited by admin on Fri Jun 25 21:34:45 UTC 2021
PRIMARY
NDF-RT
N0000185503
Created by admin on Fri Jun 25 21:34:45 UTC 2021 , Edited by admin on Fri Jun 25 21:34:45 UTC 2021
PRIMARY P-Glycoprotein Inhibitors [MoA]
NDF-RT
N0000187061
Created by admin on Fri Jun 25 21:34:45 UTC 2021 , Edited by admin on Fri Jun 25 21:34:45 UTC 2021
PRIMARY Organic Cation Transporter 2 Inhibitors [MoA]
CAS
142387-99-3
Created by admin on Fri Jun 25 21:34:45 UTC 2021 , Edited by admin on Fri Jun 25 21:34:45 UTC 2021
SUPERSEDED
NCI_THESAURUS
C66507
Created by admin on Fri Jun 25 21:34:45 UTC 2021 , Edited by admin on Fri Jun 25 21:34:45 UTC 2021
PRIMARY
EPA CompTox
95635-55-5
Created by admin on Fri Jun 25 21:34:45 UTC 2021 , Edited by admin on Fri Jun 25 21:34:45 UTC 2021
PRIMARY
NDF-RT
N0000190114
Created by admin on Fri Jun 25 21:34:45 UTC 2021 , Edited by admin on Fri Jun 25 21:34:45 UTC 2021
PRIMARY Cytochrome P450 3A Inhibitors [MoA]
WIKIPEDIA
RANOLAZINE
Created by admin on Fri Jun 25 21:34:45 UTC 2021 , Edited by admin on Fri Jun 25 21:34:45 UTC 2021
PRIMARY
DRUG BANK
DB00243
Created by admin on Fri Jun 25 21:34:45 UTC 2021 , Edited by admin on Fri Jun 25 21:34:45 UTC 2021
PRIMARY
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METABOLIC ENZYME -> SUBSTRATE
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SALT/SOLVATE -> PARENT
METABOLIC ENZYME -> SUBSTRATE
MAJOR
TRANSPORTER -> INHIBITOR
TRANSPORTER -> SUBSTRATE
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METABOLITE -> PARENT
METABOLITE -> PARENT
METABOLITE -> PARENT
METABOLITE -> PARENT
METABOLITE -> PARENT
METABOLITE -> PARENT
METABOLITE -> PARENT
METABOLITE -> PARENT
METABOLITE -> PARENT
METABOLITE -> PARENT
METABOLITE -> PARENT
primarily formed by CYP3A
MAJOR
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METABOLITE -> PARENT
METABOLITE -> PARENT
By both CYP3A and CYP2D6
MAJOR
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METABOLITE -> PARENT
METABOLITE -> PARENT
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ACTIVE MOIETY
Name Property Type Amount Referenced Substance Defining Parameters References
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PHARMACOKINETIC
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PHARMACOKINETIC