Details
Stereochemistry | RACEMIC |
Molecular Formula | C24H33N3O4.2ClH |
Molecular Weight | 500.458 |
Optical Activity | ( + / - ) |
Defined Stereocenters | 0 / 1 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
Cl.Cl.COC1=C(OCC(O)CN2CCN(CC(=O)NC3=C(C)C=CC=C3C)CC2)C=CC=C1
InChI
InChIKey=RJNSNFZXAZXOFX-UHFFFAOYSA-N
InChI=1S/C24H33N3O4.2ClH/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);2*1H
DescriptionCurator's Comment: description was created based on several sources, including
https://www.ncbi.nlm.nih.gov/pubmed/16196483
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
Sources: https://www.ncbi.nlm.nih.gov/pubmed/26950436
Curator's Comment: Known to be CNS active in rats. Human data not available
Originator
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
---|---|---|---|
Target ID: CHEMBL1980 Sources: https://www.ncbi.nlm.nih.gov/pubmed/?term=18462746 |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
---|---|---|---|---|
Primary | RANEXA Approved UseRanexa 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 Date2006 |
Cmax
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
741.5 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/23355361 |
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
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
9862.7 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/23355361 |
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
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
6.4 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/23355361 |
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
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
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
Dose | Population | Adverse 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%) Sources: Nausea (8.6%) Asthenia (6.4%) Constipation (4.3%) Angina pectoris (3.2%) Headache (2.7%) Sweating (2.7%) |
50 g single, oral Overdose Dose: 50 g Route: oral Route: single Dose: 50 g Co-administed with:: quetiapine(therapeutic or subtherapeutic) Sources: valproate(therapeutic or subtherapeutic) mirtazapine(therapeutic or subtherapeutic) |
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%) Sources: Nausea (1%) Asthenia (0.5%) Constipation (0.5%) Headache (0.5%) |
AEs
AE | Significance | Dose | Population |
---|---|---|---|
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) Sources: valproate(therapeutic or subtherapeutic) mirtazapine(therapeutic or subtherapeutic) |
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
CYP3A4 | CYP2C9 | CYP2D6 | hERG |
---|---|---|---|
Drug as perpetrator
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
Page: 12, 13 |
moderate | |||
Page: 5, 87 |
no | |||
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021526_s000_Ranexa_BioPharmr.pdf Page: 97, 145 |
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 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021526_s000_Ranexa_BioPharmr.pdf Page: 97, 145 |
||
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021526_s000_Ranexa_BioPharmr.pdf Page: 121, 315 |
yes | |||
Page: 12, 13 |
yes |
Drug as victim
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021526_s000_Ranexa_BioPharmr.pdf Page: 96, 131 |
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 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021526_s000_Ranexa_BioPharmr.pdf Page: 96, 131 |
||
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021526_s000_Ranexa_BioPharmr.pdf Page: 96, 131 |
minor | yes (co-administration study) Comment: paroxetine increased the exposure of ranolazine by <20% Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021526_s000_Ranexa_BioPharmr.pdf Page: 96, 131 |
||
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021526_s000_Ranexa_BioPharmr.pdf Page: 97, 144 |
yes |
Tox targets
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
Page: 102.0 |
PubMed
Title | Date | PubMed |
---|---|---|
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 |
|
IR, MS studies on (+/-)-1-[3-(2-methoxyphenoxy)-2-hydroxypropyl]-4-[(2,6-dimethylphenyl)aminocarbonylmethyl]piperazine dihydrochloride salt. | 2005 Feb |
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
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/26950436
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.
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Classification Tree | Code System | Code | ||
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NCI_THESAURUS |
C78322
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NCI_THESAURUS |
C93038
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100000091967
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142387-98-2
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DTXSID50904741
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SUB26173
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DBSALT000388
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m9499
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71279
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110445-25-5
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CHEMBL1404
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C66508
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F71253DJUN
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95635-56-6
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94386-66-0
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X-45
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ACTIVE MOIETY
SUBSTANCE RECORD