General
Preferred name
RANOLAZINE
Synonyms
RS-43285 ()
Ranolazine HCl ()
RANOLAZINE DIHYDROCHLORIDE ()
RANOLAZINE HYDROCHLORIDE ()
RS 43285-003 ()
CVT 303 ()
Ranexa ()
RS 43285 ()
Ranolazine 2HCl ()
Ranolazine (dihydrochloride) ()
CVT 303 (dihydrochloride) ()
RS-43285,RS 43285-193,Ranexa, renolazine,Ranolazine dihydrochloride ()
CVT 303, RS 43285-003 ()
Ran d ()
Aspruzyo sprinkle ()
NSC-759100 ()
RS-43285-003 ()
CVT-303 ()
Aspruzyo ()
Ranolazine (hydrochoride) ()
Ranolazine-d5 ()
P&D ID
PD010150
CAS
95635-56-6
142387-99-3
110445-25-5
1080496-58-7
95635-55-5
1092804-87-9
Tags
drug candidate
natural product
drug
available
Approved by
FDA
First approval
2006
Drug Status
investigational
approved
Drug indication
Anti-Anginal
Paroxysmal atrial fibrillation
Chronic/stable angina
Max Phase
Phase 4
Probe control
Probe control not defined
Orthogonal probes
0
No orthogonal probes found
Similar probes
0
No structurally similar probes found
Structure
P&D probe-likeness score
Structure formats
[[ format ]]
[[ compound[format === 'MOL' ? 'molblock' : format.toLowerCase()] ]]
Description
(extracted from source data)
METABOLISM
Ranolazine is greatly metabolized in the liver an intestine via the activity of cytochrome P450, from which the isoform CYP3A4 presents the main role and CYP2D6 presents minor importance.[A174898] The metabolism of ranolazine has reported more than 40 metabolites in plasma and more than 100 metabolites in urine.[A174946] From the observed metabolism, there are 4 major metabolites from which RS-88390, as well as the unchanged drug, are known to weakly inhibit CYP3A4. However, the activity of the metabolites of ranolazine has not been fully elucidated.[L5473]
ROE
From the administered dose, about 75% is excreted renally.[A174898] From this eliminated dose, only about 5% is represented by the unchanged drug.[A174946]
PHARMACODYNAMICS
The inhibition of the late phase sodium current can reduce the upregulated level of cytosolic calcium. The presence of intracellular calcium overload is key for the reduction of left ventricular relaxation causing ventricular tachycardia.[A174898] The effects of ranolazine on the rectifying potassium current results in prolonged QTc and transmural dispersion of repolarization without inducing ventricular arrhythmias or torsade de pointes as this effect is contrary to the effect towards the sodium channels.[A174913] It has been reported that ranolazine exerts significant depression of the action potential amplitude in atrial myocytes. The inhibition of sodium channels as well as potassium rectifiers produces an opposite reaction, the end effect is highly dependent on the cell type and the degree of contribution of these currents. It is known that sodium channels are greater in M cells and Purkinje fibers in which ranolazine can produce significant shortening of action potential duration. On the same point, ranolazine can produce prolonged action potential duration on epicardial cells and this combined effect on the three cells is the key point for the protective effect against ventricular arrhythmias.[A174913] The effect of ranolazine towards fatty acid was thought to be the main mechanism of action of this therapeutic agent as the reduction of fatty acid oxidation will in order, enhance glucose oxidation, reduce production of lactic acid and improve heart function.[A174940] However, this mechanism of action was later shown to not be the major therapeutic effect-causing mechanism. In clinical trials for stable angina (MARISA) the use of ranolazine significantly increases the exercise duration while having a negligible effect on heart rate and blood pressure. As well, in other clinical trials (CARISA) the time to angina symptoms and time to ischemia were significantly increased while the angina attacks and nitroglycerin use was reduced by about 7 days in the ranolazine-treated patients.[A174940]
MOA
Ranolazine acts by inhibiting sodium and potassium ion channel currents. This effect is obtained as a result of the inhibition of peak and late sodium channels which in order increases myocardial function.[A174898] The effect of ranolazine in sodium channels is being reported to be tissue-specific as well as frequency- and voltage-dependent for which ranolazine has been proven to be more potent in the setting of tachycardia.[A174913] As well, ranolazine inhibits delayed rectifier potassium currents with an inhibitory concentration of 11.5 microM which in order prolongs the ventricular action potential duration. As well, ranolazine has been shown to have a small activity towards L-type calcium channels making it a weak direct vasodilator and presents a minimal direct effect on atrioventricular nodal conduction.[A174913] In order, the effect of ranolazine is obtained via a combination between the inhibition of the delayed rectifier potassium currents and the inward sodium current inhibition.[A174898] Some other mechanisms have been elucidated in which ranolazine presents antagonistic activity towards the alpha1- and beta1-adrenergic in animal models as well as an inhibitory profile against fatty acid oxidation.[A174898]
INDICATION
Ranolazine is approved as a second-line agent in the management of chronic stable angina pectoris that is refractory to conventional anti-ischemic therapy.[A174913] Ranolazine has also been used off-label for the treatment of some arrhythmias such as ventricular tachycardia, however, this use does not have a lot of supporting evidence.[A174940] The use of ranolazine has been researched in the treatment of acute coronary syndrome, microvascular coronary dysfunction, arrhythmia, and glycemic control.[A174898]
TOXICITY
The reported LD50 of oral ranolazine in the rat is of 980 mg/kg.[MSDS] Overdose oral administration of ranolazine is observed as an increase in dizziness, nausea, and vomiting while intravenous administration can also produce diplopia, paresthesia, confusion, and syncope. In events of overdose, ECG monitoring is recommended.[FDA label] Ranolazine was shown to lack genotoxic and carcinogenic potential. However, fertility studies reported an increased incidence of misshapen sternebrae and reduced ossification of pelvic and cranial bones.[FDA label]
ABSORPTION
The time to reach peak serum concentration is very variable but it has been suggested to be of 2-6 hours and to reach steady-state within 3 days.[A174898] The absorption of ranolazine is not modified by food consumption.[A174940] The bioavailability of ranolazine is reported to be of about 73% counting both the unchanged form and the metabolites. After multiple administration of a dose of 500 mg, the reported Cmax and AUC were 1770 ng/ml and 13700 ng.h/ml respectively.[L5473]
HALF-LIFE
Due to the short half-life of the immediate release formulation of ranolazine (1.4-1.9 hours), it was required the generation of an extended-release formulation which presented an approximate steady-state half-life of 7-9 hours.[A174898]
MOA
Ranolazine acts by inhibiting sodium and potassium ion channel currents. This effect is obtained as a result of the inhibition of peak and late sodium channels which in order increases myocardial function.[A174898] The effect of ranolazine in sodium channels is being reported to be tissue-specific as well as frequency- and voltage-dependent for which ranolazine has been proven to be more potent in the setting of tachycardia.[A174913] ; ; As well, ranolazine inhibits delayed rectifier potassium currents with an inhibitory concentration of 11.5 microM which in order prolongs the ventricular action potential duration. As well, ranolazine has been shown to have a small activity towards L-type calcium channels making it a weak direct vasodilator and presents a minimal direct effect on atrioventricular nodal conduction.[A174913]; ; In order, the effect of ranolazine is obtained via a combination between the inhibition of the delayed rectifier potassium currents and the inward sodium current inhibition.[A174898]; ; Some other mechanisms have been elucidated in which ranolazine presents antagonistic activity towards the alpha1- and beta1-adrenergic in animal models as well as an inhibitory profile against fatty acid oxidation.[A174898]
INDICATION
Ranolazine is approved as a second-line agent in the management of chronic stable angina pectoris that is refractory to conventional anti-ischemic therapy.[A174913]; ; Ranolazine has also been used off-label for the treatment of some arrhythmias such as ventricular tachycardia, however, this use does not have a lot of supporting evidence.[A174940]; ; The use of ranolazine has been researched in the treatment of acute coronary syndrome, microvascular coronary dysfunction, arrhythmia, and glycemic control.[A174898]
METABOLISM
Ranolazine is greatly metabolized in the liver an intestine via the activity of cytochrome P450, from which the isoform CYP3A4 presents the main role and CYP2D6 presents minor importance.[A174898] The metabolism of ranolazine has reported more than 40 metabolites in plasma and more than 100 metabolites in urine.[A174946] ; ; From the observed metabolism, there are 4 major metabolites from which RS-88390, as well as the unchanged drug, are known to weakly inhibit CYP3A4. However, the activity of the metabolites of ranolazine has not been fully elucidated.[L5473]
DESCRIPTION
The mechanism of action of ranolazine is largely unknown, but may have some antianginal effects by inhibition of the late sodium current in cardiac cells.
(GtoPdb)
PHARMACODYNAMICS
The inhibition of the late phase sodium current can reduce the upregulated level of cytosolic calcium. The presence of intracellular calcium overload is key for the reduction of left ventricular relaxation causing ventricular tachycardia.[A174898]; ; The effects of ranolazine on the rectifying potassium current results in prolonged QTc and transmural dispersion of repolarization without inducing ventricular arrhythmias or torsade de pointes as this effect is contrary to the effect towards the sodium channels.[A174913]; ; It has been reported that ranolazine exerts significant depression of the action potential amplitude in atrial myocytes. The inhibition of sodium channels as well as potassium rectifiers produces an opposite reaction, the end effect is highly dependent on the cell type and the degree of contribution of these currents. It is known that sodium channels are greater in M cells and Purkinje fibers in which ranolazine can produce significant shortening of action potential duration. On the same point, ranolazine can produce prolonged action potential duration on epicardial cells and this combined effect on the three cells is the key point for the protective effect against ventricular arrhythmias.[A174913]; ; The effect of ranolazine towards fatty acid was thought to be the main mechanism of action of this therapeutic agent as the reduction of fatty acid oxidation will in order, enhance glucose oxidation, reduce production of lactic acid and improve heart function.[A174940] However, this mechanism of action was later shown to not be the major therapeutic effect-causing mechanism.; ; In clinical trials for stable angina (MARISA) the use of ranolazine significantly increases the exercise duration while having a negligible effect on heart rate and blood pressure. As well, in other clinical trials (CARISA) the time to angina symptoms and time to ischemia were significantly increased while the angina attacks and nitroglycerin use was reduced by about 7 days in the ranolazine-treated patients.[A174940]
TOXICITY
The reported LD50 of oral ranolazine in the rat is of 980 mg/kg.[MSDS] Overdose oral administration of ranolazine is observed as an increase in dizziness, nausea, and vomiting while intravenous administration can also produce diplopia, paresthesia, confusion, and syncope. In events of overdose, ECG monitoring is recommended.[FDA label]; ; Ranolazine was shown to lack genotoxic and carcinogenic potential. However, fertility studies reported an increased incidence of misshapen sternebrae and reduced ossification of pelvic and cranial bones.[FDA label]
DESCRIPTION
Cdk1 and cdk2 inhibitor
(Tocris Bioactive Compound Library)
DESCRIPTION
Antianginal, activates pyruvate dehydrogenase
(Tocriscreen Plus)
DESCRIPTION
pFOX (partial fatty acid oxidation) inhibitor
(LOPAC library)
DESCRIPTION
Ranolazine 2HCl is a calcium uptake inhibitor via the sodium/calcium channal, used to treat chronic angina.
(BOC Sciences Bioactive Compounds)
[[ p.pathway_name ]]
[[ compound.targets[tid].gene_name ]]
Cell lines
0
Organisms
1
Compound Sets
30
AdooQ Bioactive Compound Library
Axon Medchem Screening Library
BOC Sciences Bioactive Compounds
CeMM library of unique drugs (CLOUD)
ChEMBL Approved Drugs
ChEMBL Drugs
DrugBank
DrugBank Approved Drugs
DrugCentral
DrugCentral Approved Drugs
DrugMAP
DrugMAP Approved Drugs
DrugMatrix
Enamine BioReference Compounds
Guide to Pharmacology
LOPAC library
Mcule NIBR MoA Box Subset
NCATS Inxight Approved Drugs
NIH Clinical Collections (NCC)
Novartis Chemogenetic Library (NIBR MoA Box)
NPC Screening Collection
Prestwick Chemical Library
ReFrame library
Selleckchem Bioactive Compound Library
The Spectrum Collection
Tocris Bioactive Compound Library
Tocriscreen Plus
[[ a.name ]]
[[ ligand_id ]]
free of charge
External IDs
64
Molecular Weight
427.25
Hydrogen Bond Acceptors
6
Hydrogen Bond Donors
2
Rotatable Bonds
9
Ring Count
3
Aromatic Ring Count
2
cLogP
2.31
TPSA
74.27
Fraction CSP3
0.46
Chiral centers
1.0
Largest ring
6.0
QED
0.64
Structural alerts
0
No structural alerts detected
Related compounds
Custom attributes
(extracted from source data)
Target
Sodium channel protein type V alpha subunit
Sodium channel protein type IV alpha subunit
Calcium Channel
Sodium Channel
Ca2+/K+/Na+ blocker
Target Type
Enzymes
Selectivity
pFOX
MOA
Unknown molecular target
Activator
Sodium Channel Blockers
Pathway
Membrane Transporter/Ion Channel
Autophagy
Neuronal Signaling
Primary Target
Other Dehydrogenases
Member status
member
Therapeutic Class
Analgesics
Source data
