Rasagiline

Identification

Summary

Rasagiline is an irreversible inhibitor of monoamine oxidase used for the symptomatic management of idiopathic Parkinson's disease as initial monotherapy and as adjunct therapy to levodopa.

Brand Names
Azilect
Generic Name
Rasagiline
DrugBank Accession Number
DB01367
Background

Rasagiline is an irreversible inhibitor of monoamine oxidase and is used as a monotherapy in early Parkinson's disease or as an adjunct therapy in more advanced cases.

Type
Small Molecule
Groups
Approved
Structure
Thumb
Weight
Average: 171.2383
Monoisotopic: 171.104799421
Chemical Formula
C12H13N
Synonyms
  • (1R)-N-propargylindan-1-amine
  • (R)-indan-1-yl-prop-2-ynyl-amine
  • (R)-N-2-Propynyl-1-indanamine
  • RAS
  • Rasagilina
  • Rasagiline
External IDs
  • AGN-1135
  • TV-1030

Pharmacology

Indication

For the treatment of the signs and symptoms of idiopathic Parkinsons disease as initial monotherapy and as adjunct therapy to levodopa.

Pharmacology
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Associated Conditions
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Contraindications
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Pharmacodynamics

Rasagiline is a propargylamine and an irreversible inhibitor of monoamine oxidase (MAO). MAO, a flavin-containing enzyme, regulates the metabolic degradation of catecholamines and serotonin in the CNS and peripheral tissues. It is classified into two major molecular species, A and B, and is localized in mitochondrial membranes throughout the body in nerve terminals, brain, liver and intestinal mucosa. MAO-A is found predominantly in the GI tract and liver, and regulates the metabolic degradation of circulating catecholamines and dietary amines. MAO-B is the major form in the human brain and is responsible for the regulation of the metabolic degradation of dopamine and phenylethylamine. In ex vivo animal studies in brain, liver and intestinal tissues rasagiline was shown to be a potent,selective, and irreversible monoamine oxidase type B (MAO-B) inhibitor. At the recommended therapeutic doses, Rasagiline was also shown to be a potent and irreversible inhibitor of MAO-B in platelets. The selectivity of rasagiline for inhibiting only MAO-B (and not MAO-A) in humans and the sensitivity to tyramine during rasagiline treatment at any dose has not been sufficiently characterized to avoid restriction of dietary tyramine and amines contained in medications.

Mechanism of action

The precise mechanisms of action of rasagiline is unknown. One mechanism is believed to be related to its MAO-B inhibitory activity, which causes an increase in extracellular levels of dopamine in the striatum. The elevated dopamine level and subsequent increased dopaminergic activity are likely to mediate rasagiline's beneficial effects seen in models of dopaminergic motor dysfunction.

TargetActionsOrganism
AAmine oxidase [flavin-containing] B
inhibitor
Humans
AApoptosis regulator Bcl-2
activator
Humans
Absorption

Rasagiline is rapidly absorbed following oral administration. The absolute bioavailability of rasagiline is about 36%.

Volume of distribution
  • 87 L
Protein binding

Plasma protein binding ranges from 88-94% with mean extent of binding of 61-63% to human albumin over the concentration range of 1-100 ng/ml.

Metabolism

Rasagiline undergoes almost complete biotransformation in the liver prior to excretion. In vitro experiments indicate that both routes of rasagiline metabolism are dependent on the cytochrome P450 (CYP) system, with CYP 1A2 being the major isoenzyme involved in rasagiline metabolism.

Route of elimination

Rasagiline undergoes almost complete biotransformation in the liver prior to excretion. Glucuronide conjugation of rasagiline and its metabolites, with subsequent urinary excretion, is the major elimination pathway. After oral administration of 14C-labeled rasagiline, elimination occurred primarily via urine and secondarily via feces (62% of total dose in urine and 7% of total dose in feces over 7 days), with a total calculated recovery of 84% of the dose over a period of 38 days. Less than 1% of rasagiline was excreted as unchanged drug in urine.

Half-life

Rasagiline has a mean steady-state half life of 3 hours but there is no correlation of pharmacokinetics with its pharmacological effect because of its irreversible inhibition of MAO-B.

Clearance

Not Available

Adverse Effects
Adverseeffects
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Toxicity

Signs and symptoms of overdosage may include, alone or in combination, any of the following: drowsiness, dizziness, faintness, irritability, hyperactivity, agitation, severe headache, hallucinations, trismus, opisthotonos, convulsions, and coma; rapid and irregular pulse, hypertension, hypotension and vascular collapse; precordial pain, respiratory depression and failure, hyperpyrexia, diaphoresis, and cool, clammy skin.

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
1,2-BenzodiazepineThe risk or severity of adverse effects can be increased when Rasagiline is combined with 1,2-Benzodiazepine.
AbacavirAbacavir may decrease the excretion rate of Rasagiline which could result in a higher serum level.
AbametapirThe serum concentration of Rasagiline can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Rasagiline can be increased when combined with Abatacept.
AbciximabThe risk or severity of bleeding and hemorrhage can be increased when Rasagiline is combined with Abciximab.
AbirateroneThe serum concentration of Rasagiline can be increased when it is combined with Abiraterone.
AcarboseRasagiline may increase the hypoglycemic activities of Acarbose.
AcebutololRasagiline may increase the hypotensive activities of Acebutolol.
AceclofenacThe risk or severity of hypertension can be increased when Rasagiline is combined with Aceclofenac.
AcemetacinThe risk or severity of hypertension can be increased when Rasagiline is combined with Acemetacin.
Interactions
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Food Interactions
  • Avoid St. John's Wort. Co-administration of rasagiline with this herb is contraindicated.
  • Avoid tyramine-containing foods and supplements. Avoid food containing high amounts of tyramine (>150mg) as these may increase the risk of hypertensive reaction. Tyramine-containing foods include cheese, red wine, fava beans, pickled food, cured food, and alcoholic beverages.
  • Take with or without food.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Rasagiline mesylateLH8C2JI290161735-79-1JDBJJCWRXSVHOQ-UTONKHPSSA-N
Rasagiline tartrateB9A329CN07136236-52-7YGKHOZXCTLKSLJ-KHAGDFGNSA-N
Product Images
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Asn-rasagilineTablet1 mgOralAscend Laboratories LtdNot applicableNot applicableCanada flag
Asn-rasagilineTablet0.5 mgOralAscend Laboratories LtdNot applicableNot applicableCanada flag
AzilectTablet1 mgOralTeva B.V.2020-12-16Not applicableEU flag
AzilectTablet1 mg/1OralAphena Pharma Solutions Tennessee, Inc.2006-07-10Not applicableUS flag
AzilectTablet1 mgOralTeva B.V.2020-12-16Not applicableEU flag
AzilectTablet1 mgOralTeva B.V.2020-12-16Not applicableEU flag
AzilectTablet1 mgOralTEVA Canada Limited2006-09-14Not applicableCanada flag
AzilectTablet1 mg/1OralTeva Neuroscience, Inc.2006-07-10Not applicableUS flag68546 022920210407 15418 vhj17z
AzilectTablet1 mgOralTeva B.V.2020-12-16Not applicableEU flag
AzilectTablet1 mg/1OralPhysicians Total Care, Inc.2010-12-03Not applicableUS flag68546 0229 56 nlmimage10 402d2059
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Ag-rasagilineTablet1 mgOralAngita Pharma Inc.Not applicableNot applicableCanada flag
Ag-rasagilineTablet0.5 mgOralAngita Pharma Inc.Not applicableNot applicableCanada flag
Apo-rasagilineTablet1 mgOralApotex Corporation2016-01-12Not applicableCanada flag
Apo-rasagilineTablet0.5 mgOralApotex Corporation2016-01-12Not applicableCanada flag
Jamp RasagilineTablet1 mgOralJamp Pharma Corporation2020-09-04Not applicableCanada flag
Jamp RasagilineTablet0.5 mgOralJamp Pharma Corporation2020-09-04Not applicableCanada flag
RasagilineTablet1 mg/1OralMicro Labs Limited2019-04-03Not applicableUS flag
RasagilineTablet0.5 mg/1OralNorthstar RxLLC2018-04-17Not applicableUS flag
RasagilineTablet1 mg/1OralAvKARE2021-05-20Not applicableUS flag
RasagilineTablet1 mg/1OralTeva Pharmaceuticals USA, Inc.2017-01-03Not applicableUS flag

Categories

ATC Codes
N04BD02 — Rasagiline
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as indanes. These are compounds containing an indane moiety, which consists of a cyclopentane fused to a benzene ring.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Indanes
Sub Class
Not Available
Direct Parent
Indanes
Alternative Parents
Aralkylamines / Dialkylamines / Acetylides / Organopnictogen compounds / Hydrocarbon derivatives
Substituents
Acetylide / Amine / Aralkylamine / Aromatic homopolycyclic compound / Hydrocarbon derivative / Indane / Organic nitrogen compound / Organonitrogen compound / Organopnictogen compound / Secondary aliphatic amine
Molecular Framework
Aromatic homopolycyclic compounds
External Descriptors
terminal acetylenic compound, secondary amine, indanes (CHEBI:63620)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
003N66TS6T
CAS number
136236-51-6
InChI Key
RUOKEQAAGRXIBM-GFCCVEGCSA-N
InChI
InChI=1S/C12H13N/c1-2-9-13-12-8-7-10-5-3-4-6-11(10)12/h1,3-6,12-13H,7-9H2/t12-/m1/s1
IUPAC Name
(1R)-N-(prop-2-yn-1-yl)-2,3-dihydro-1H-inden-1-amine
SMILES
C#CCN[C@@H]1CCC2=CC=CC=C12

References

Synthesis Reference

Jeffrey Sterling, David Lerner, Harel Rosen, Leonid Bronov, Dalia Medini-Green, Berta Iosefzon, Tirtsah Berger-Peskin, Ramy Lidor-Hadas, Eliezer Bahar, "Rasagiline formulations and processes for their preparation." U.S. Patent US07598420, issued October 06, 2009.

US07598420
General References
  1. Weinreb O, Amit T, Bar-Am O, Youdim MB: Rasagiline: a novel anti-Parkinsonian monoamine oxidase-B inhibitor with neuroprotective activity. Prog Neurobiol. 2010 Nov;92(3):330-44. doi: 10.1016/j.pneurobio.2010.06.008. Epub 2010 Jun 19. [Article]
  2. Leegwater-Kim J, Bortan E: The role of rasagiline in the treatment of Parkinson's disease. Clin Interv Aging. 2010 May 25;5:149-56. [Article]
  3. Chen JJ, Swope DM, Dashtipour K: Comprehensive review of rasagiline, a second-generation monoamine oxidase inhibitor, for the treatment of Parkinson's disease. Clin Ther. 2007 Sep;29(9):1825-49. [Article]
Human Metabolome Database
HMDB0015454
KEGG Drug
D08469
PubChem Compound
3052776
PubChem Substance
46506045
ChemSpider
2314553
BindingDB
10989
RxNav
134748
ChEBI
63620
ChEMBL
CHEMBL887
ZINC
ZINC000019875504
Therapeutic Targets Database
DAP001107
PharmGKB
PA164764584
PDBe Ligand
RAU
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Rasagiline
PDB Entries
5g6s
FDA label
Download (200 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedTreatmentDepressive Symptomatology / Parkinson's Disease (PD)1
4CompletedTreatmentParkinson's Disease (PD)8
4CompletedTreatmentParkinson's Disease (PD) / Sleep Disturbance1
4CompletedTreatmentSchizophrenia1
4TerminatedSupportive CareRetinal Detachment1
4TerminatedTreatmentEarly Stage Parkinson's Disease1
4TerminatedTreatmentParkinson's Disease (PD)1
4Unknown StatusTreatmentApathy / Drug-naïve Patients With Parkinson's Disease1
4Unknown StatusTreatmentParkinson's Disease (PD)3
3Active Not RecruitingTreatmentEarly Parkinson's Disease / Parkinson's Disease (PD)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • Murfreesboro Pharmaceutical Nursing Supply
  • Teva Pharmaceutical Industries Ltd.
Dosage Forms
FormRouteStrength
TabletOral0.5 mg
TabletOral1 mg/1
Tablet, film coated
TabletOral
TabletOral0.5 mg/1
TabletOral1 mg
Prices
Unit descriptionCostUnit
Azilect 0.5 mg tablet12.11USD tablet
Azilect 1 mg tablet12.11USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US5387612No1995-02-072012-02-07US flag
CA2232310No2008-01-082016-09-18Canada flag
CA2031714No1998-08-252010-12-06Canada flag
US5453446No1995-09-262017-02-07US flag
US7815942No2010-10-192027-08-27US flag
US7572834No2009-08-112026-12-05US flag
US6126968No2000-10-032016-09-18US flag

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0249 mg/mLALOGPS
logP2.26ALOGPS
logP2.3ChemAxon
logS-3.8ALOGPS
pKa (Strongest Basic)8.69ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count1ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area12.03 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity54.47 m3·mol-1ChemAxon
Polarizability20.25 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.9901
Blood Brain Barrier+0.9782
Caco-2 permeable+0.5585
P-glycoprotein substrateNon-substrate0.661
P-glycoprotein inhibitor INon-inhibitor0.7409
P-glycoprotein inhibitor IINon-inhibitor0.7116
Renal organic cation transporterNon-inhibitor0.5584
CYP450 2C9 substrateNon-substrate0.8037
CYP450 2D6 substrateSubstrate0.5724
CYP450 3A4 substrateNon-substrate0.6928
CYP450 1A2 substrateInhibitor0.9037
CYP450 2C9 inhibitorNon-inhibitor0.8259
CYP450 2D6 inhibitorInhibitor0.6769
CYP450 2C19 inhibitorInhibitor0.5689
CYP450 3A4 inhibitorNon-inhibitor0.8542
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.534
Ames testNon AMES toxic0.6468
CarcinogenicityNon-carcinogens0.8959
BiodegradationNot ready biodegradable0.6073
Rat acute toxicity2.8164 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.7804
hERG inhibition (predictor II)Non-inhibitor0.7137
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

Targets

Drugtargets2
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Primary amine oxidase activity
Specific Function
Catalyzes the oxidative deamination of biogenic and xenobiotic amines and has important functions in the metabolism of neuroactive and vasoactive amines in the central nervous system and peripheral...
Gene Name
MAOB
Uniprot ID
P27338
Uniprot Name
Amine oxidase [flavin-containing] B
Molecular Weight
58762.475 Da
References
  1. Naoi M, Maruyama W: Functional mechanism of neuroprotection by inhibitors of type B monoamine oxidase in Parkinson's disease. Expert Rev Neurother. 2009 Aug;9(8):1233-50. doi: 10.1586/ern.09.68. [Article]
  2. Uzun M, Alp R, Uzlu E, Alp S, Citil M, Topcu B, Erdogan HM: Investigation of oral selegiline and rasagiline administration on QT interval in conscious rabbits. Eur Rev Med Pharmacol Sci. 2009 Mar-Apr;13(2):95-8. [Article]
  3. Youdim MB, Weinstock M: Molecular basis of neuroprotective activities of rasagiline and the anti-Alzheimer drug TV3326 [(N-propargyl-(3R)aminoindan-5-YL)-ethyl methyl carbamate]. Cell Mol Neurobiol. 2001 Dec;21(6):555-73. [Article]
  4. Chau KY, Cooper JM, Schapira AH: Rasagiline protects against alpha-synuclein induced sensitivity to oxidative stress in dopaminergic cells. Neurochem Int. 2010 Nov;57(5):525-9. doi: 10.1016/j.neuint.2010.06.017. Epub 2010 Jul 17. [Article]
  5. Weinreb O, Amit T, Bar-Am O, Youdim MB: Rasagiline: a novel anti-Parkinsonian monoamine oxidase-B inhibitor with neuroprotective activity. Prog Neurobiol. 2010 Nov;92(3):330-44. doi: 10.1016/j.pneurobio.2010.06.008. Epub 2010 Jun 19. [Article]
  6. Youdim MB, Bar Am O, Yogev-Falach M, Weinreb O, Maruyama W, Naoi M, Amit T: Rasagiline: neurodegeneration, neuroprotection, and mitochondrial permeability transition. J Neurosci Res. 2005 Jan 1-15;79(1-2):172-9. [Article]
  7. Leegwater-Kim J, Bortan E: The role of rasagiline in the treatment of Parkinson's disease. Clin Interv Aging. 2010 May 25;5:149-56. [Article]
  8. Chen JJ, Swope DM, Dashtipour K: Comprehensive review of rasagiline, a second-generation monoamine oxidase inhibitor, for the treatment of Parkinson's disease. Clin Ther. 2007 Sep;29(9):1825-49. [Article]
  9. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Activator
General Function
Ubiquitin protein ligase binding
Specific Function
Suppresses apoptosis in a variety of cell systems including factor-dependent lymphohematopoietic and neural cells. Regulates cell death by controlling the mitochondrial membrane permeability. Appea...
Gene Name
BCL2
Uniprot ID
P10415
Uniprot Name
Apoptosis regulator Bcl-2
Molecular Weight
26265.66 Da
References
  1. Youdim MB, Weinstock M: Molecular basis of neuroprotective activities of rasagiline and the anti-Alzheimer drug TV3326 [(N-propargyl-(3R)aminoindan-5-YL)-ethyl methyl carbamate]. Cell Mol Neurobiol. 2001 Dec;21(6):555-73. [Article]
  2. Akao Y, Maruyama W, Yi H, Shamoto-Nagai M, Youdim MB, Naoi M: An anti-Parkinson's disease drug, N-propargyl-1(R)-aminoindan (rasagiline), enhances expression of anti-apoptotic bcl-2 in human dopaminergic SH-SY5Y cells. Neurosci Lett. 2002 Jun 28;326(2):105-8. [Article]
  3. Maruyama W, Akao Y, Carrillo MC, Kitani K, Youdium MB, Naoi M: Neuroprotection by propargylamines in Parkinson's disease: suppression of apoptosis and induction of prosurvival genes. Neurotoxicol Teratol. 2002 Sep-Oct;24(5):675-82. [Article]
  4. Youdim MB, Amit T, Falach-Yogev M, Bar Am O, Maruyama W, Naoi M: The essentiality of Bcl-2, PKC and proteasome-ubiquitin complex activations in the neuroprotective-antiapoptotic action of the anti-Parkinson drug, rasagiline. Biochem Pharmacol. 2003 Oct 15;66(8):1635-41. [Article]
  5. Bar-Am O, Weinreb O, Amit T, Youdim MB: Regulation of Bcl-2 family proteins, neurotrophic factors, and APP processing in the neurorescue activity of propargylamine. FASEB J. 2005 Nov;19(13):1899-901. Epub 2005 Sep 7. [Article]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
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 oxidizes a variety of structurally un...
Gene Name
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
References
  1. Lecht S, Haroutiunian S, Hoffman A, Lazarovici P: Rasagiline - a novel MAO B inhibitor in Parkinson's disease therapy. Ther Clin Risk Manag. 2007 Jun;3(3):467-74. [Article]
  2. Leegwater-Kim J, Bortan E: The role of rasagiline in the treatment of Parkinson's disease. Clin Interv Aging. 2010 May 25;5:149-56. [Article]
  3. Chen JJ, Swope DM, Dashtipour K: Comprehensive review of rasagiline, a second-generation monoamine oxidase inhibitor, for the treatment of Parkinson's disease. Clin Ther. 2007 Sep;29(9):1825-49. [Article]
  4. Rasagiline FDA label [File]

Drug created on June 13, 2005 13:24 / Updated on September 19, 2021 19:53