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Identification
NameRasagiline
Accession NumberDB01367  (EXPT02758)
Typesmall molecule
Groupsapproved
Description

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.

Structure
Thumb
Synonyms
SynonymLanguageCode
RASNot AvailableNot Available
SaltsNot Available
Brand names
NameCompany
AzilectNot Available
Brand mixturesNot Available
Categories
CAS number136236-51-6
WeightAverage: 171.2383
Monoisotopic: 171.104799421
Chemical FormulaC12H13N
InChI KeyRUOKEQAAGRXIBM-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
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassBenzenoids
ClassIndanes
SubclassNot Available
Direct parentIndanes
Alternative parentsBenzene and Substituted Derivatives; Dialkylamines; Polyamines
Substituentsbenzene; secondary aliphatic amine; polyamine; secondary amine; amine; organonitrogen compound
Classification descriptionThis compound belongs to the indanes. These are compounds containing an indane moiety, which consists of a cyclopentane fused to a benzene ring.
Pharmacology
IndicationFor the treatment of the signs and symptoms of idiopathic Parkinsons disease as initial monotherapy and as adjunct therapy to levodopa.
PharmacodynamicsRasagiline 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 actionThe 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.
AbsorptionRasagiline is rapidly absorbed following oral administration. The absolute bioavailability of rasagiline is about 36%.
Volume of distribution
  • 87 L
Protein bindingPlasma 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 eliminationRasagiline 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 lifeRasagiline 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.
ClearanceNot Available
ToxicitySigns 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.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.9901
Blood Brain Barrier + 0.9782
Caco-2 permeable + 0.5585
P-glycoprotein substrate Non-substrate 0.661
P-glycoprotein inhibitor I Non-inhibitor 0.7409
P-glycoprotein inhibitor II Non-inhibitor 0.7116
Renal organic cation transporter Non-inhibitor 0.5584
CYP450 2C9 substrate Non-substrate 0.8037
CYP450 2D6 substrate Substrate 0.5724
CYP450 3A4 substrate Non-substrate 0.6928
CYP450 1A2 substrate Inhibitor 0.9037
CYP450 2C9 substrate Non-inhibitor 0.8259
CYP450 2D6 substrate Inhibitor 0.6769
CYP450 2C19 substrate Inhibitor 0.5689
CYP450 3A4 substrate Non-inhibitor 0.8542
CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.534
Ames test Non AMES toxic 0.6468
Carcinogenicity Non-carcinogens 0.8959
Biodegradation Not ready biodegradable 0.6073
Rat acute toxicity 2.8164 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.7804
hERG inhibition (predictor II) Non-inhibitor 0.7137
Pharmacoeconomics
Manufacturers
  • Teva neuroscience inc
Packagers
Dosage forms
FormRouteStrength
TabletOral
TabletOral0.5 mg
TabletOral1 mg
Prices
Unit descriptionCostUnit
Azilect 0.5 mg tablet12.11USDtablet
Azilect 1 mg tablet12.11USDtablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
United States75728342006-12-052026-12-05
United States53876121995-02-072012-02-07
Canada22323102008-01-082016-09-18
Canada20317141998-08-252010-12-06
Properties
Statesolid
Experimental PropertiesNot Available
Predicted Properties
PropertyValueSource
water solubility2.49e-02 g/lALOGPS
logP2.26ALOGPS
logP2.3ChemAxon
logS-3.8ALOGPS
pKa (strongest basic)8.69ChemAxon
physiological charge1ChemAxon
hydrogen acceptor count1ChemAxon
hydrogen donor count1ChemAxon
polar surface area12.03ChemAxon
rotatable bond count2ChemAxon
refractivity54.47ChemAxon
polarizability20.25ChemAxon
number of rings2ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterYesChemAxon
Veber's ruleYesChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot Available
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 Reference
  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 Jun 19. Pubmed
  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. Pubmed
  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. Pubmed
External Links
ResourceLink
KEGG DrugD02562
PubChem Compound3052776
PubChem Substance46506045
ChemSpider2314553
BindingDB10989
Therapeutic Targets DatabaseDAP001107
PharmGKBPA164764584
HETRAS
Drug Product Database2284642
RxListhttp://www.rxlist.com/cgi/generic/azilect.htm
Drugs.comhttp://www.drugs.com/cdi/rasagiline.html
WikipediaRasagiline
ATC CodesN04BD02
AHFS Codes
  • 28:92.00
PDB Entries
FDA labelshow(200 KB)
MSDSNot Available
Interactions
Drug Interactions
Drug
AltretamineRisk of severe hypotension
AmitriptylinePossibility of severe adverse effects
AmoxapinePossibility of severe adverse effects
AmphetaminePossible hypertensive crisis
AtomoxetinePossible severe adverse reaction with this combination
BenzphetamineMAO Inhibitors may enhance the hypertensive effect of Amphetamines. Concomitant use of amphetamines and monoamine oxidase inhibitors (MAOI) should be avoided. If used concomitantly, careful monitoring of blood pressure must occur. It may take up to 2 weeks after the discontinuation of an MAOI for the effects to dissipate enough to afford safety to the administration of interacting agents.
BezafibrateMAO Inhibitors may enhance the adverse/toxic effect of Bezafibrate. Avoid concomitant use of bezafibrate with monoamine oxidase inhibitors (MAOIs) rasagiline.
BrimonidineMAO Inhibitors like rasagiline may enhance the hypertensive effect of Alpha2-Agonists (Ophthalmic). The concomitant use of monoamine oxidase inhibitors and ophthalmic alpha2 agonists is contraindicated.
BuprenorphineBuprenorphine may enhance the adverse/toxic effect of MAO Inhibitors like rasagiline. When possible, avoid use of buprenorphine in patients who have used a monoamine oxidase inhibitor within the past 14 days due to possible severe adverse effects.
BupropionPossible severe adverse reaction with this combination
BuspironePossible blood pressure elevation
CiprofloxacinCiprofloxacin, a strong CYP1A2 inhibitor, may decrease the metabolism of rasagiline. Monitor for changes in the therapeutic and adverse effects of rasagiline if ciprofloxacin is initiated or discontinued.
CitalopramPossible severe adverse reaction with this combination
ClomipraminePossibility of severe adverse effects
CyclobenzaprineIncreased risk of toxicity with this association
DesipraminePossibility of severe adverse effects
DesvenlafaxineIncreased risk of serotonin syndrome. Ensure adequate washout period between therapies to avoid toxicity. Concurrent therapy should be avoided.
DexfenfluraminePossible hypertensive crisis
DextroamphetaminePossible hypertensive crisis
DextromethorphanPossible severe adverse reaction
DiethylpropionPossible hypertensive crisis
DobutamineIncreased arterial pressure
DopamineIncreased arterial pressure
DoxepinPossibility of severe adverse effects
DuloxetinePossible severe adverse reaction with this combination
EphedraIncreased arterial pressure
EphedrineIncreased arterial pressure
EpinephrineIncreased arterial pressure
EscitalopramPossible severe adverse reaction with this combination
FenfluraminePossible hypertensive crisis
FenoterolIncreased arterial pressure
FluoxetinePossible severe adverse reaction with this combination
FluvoxaminePossible severe adverse reaction with this combination
ImipraminePossibility of severe adverse effects
IsoprenalineIncreased arterial pressure
MazindolPossible hypertensive crisis
MephentermineIncreased arterial pressure
MetaraminolIncreased arterial pressure
MethamphetaminePossible hypertensive crisis
MethoxamineIncreased arterial pressure
MethylphenidatePossible hypertensive crisis with this combination.
MidodrineRisk of hypertensive crisis.
MilnacipranIncrease serotonin levels. Combination therapy is contraindicated.
MirtazapinePossible severe adverse reaction with this combination
NefazodonePossible severe adverse reaction with this combination
NorepinephrineIncreased arterial pressure
NortriptylinePossibility of severe adverse effects
OrciprenalineIncreased arterial pressure
ParoxetinePossible severe adverse reaction with this combination
PethidineIncreased risk of serotonin syndrome. Concomitant use should be avoided.
PhendimetrazinePossible hypertensive crisis
PhenmetrazinePossible hypertensive crisis
PhenterminePossible hypertensive crisis
PhenylephrineIncreased arterial pressure
PhenylpropanolamineIncreased arterial pressure
PirbuterolIncreased arterial pressure
ProcaterolIncreased arterial pressure
ProtriptylinePossibility of severe adverse effects
PseudoephedrineIncreased arterial pressure
SalbutamolIncreased arterial pressure
SertralinePossible severe adverse reaction with this combination
SibutraminePossible serotoninergic syndrome with this combination
St. John's WortIncreased risk of toxicity with this association
TapentadolIncreases the toxicity of tapentadol by unknown mechanism. Discontinue rasagiline at least 14 days prior to tapentadol administration.
TerbutalineIncreased arterial pressure
TetrabenazineTetrabenazine may increase the adverse/toxic effects of Rasagiline. Concomitant therapy is contraindicated.
TolcaponeTolcapone and Rasagiline decrease the metabolism of endogenous catecholamines. Concomitant therapy may result in increased catecholamine effects. Consider alternate therapy or use cautiously and monitor for increased catecholamine effects.
TramadolTramadol may increase the risk of serotonin syndrome and seizure induction by the MAO inhibitor, rasagiline.
TranylcypromineIncreased risk of serotonin syndrome. Use caution during concomitant therapy and monitor for symptoms of serotonin syndrome.
TrazodoneIncreased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.
TrimipramineIncreased risk of serotonin syndrome. Ensure adequate washout period between therapies to avoid toxicity. Avoid combination or monitor for symptoms of serotonin syndrome and/or hypertensive crisis.
VenlafaxineIncreased risk of serotonin syndrome. Ensure adequate washout period between therapies to avoid toxicity. Concurrent therapy should be avoided.
ZolmitriptanThe MAO inhibitor, rasagiline, may increase the serum concentration of zolmitriptan by decreasing its metabolism. Concomitant therapy and use of zolmitriptan within two weeks of discontinuing rasagiline are contraindicated.
Food Interactions
  • Avoid alcohol and caffeine.

Targets

1. Amine oxidase [flavin-containing] B

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Amine oxidase [flavin-containing] B P27338 Details

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. Pubmed
  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. Pubmed
  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. Pubmed
  4. Chau KY, Cooper JM, Schapira AH: Rasagiline protects against alpha-synuclein induced sensitivity to oxidative stress in dopaminergic cells. Neurochem Int. 2010 Jul 17. Pubmed
  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 Jun 19. Pubmed
  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. Pubmed
  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. Pubmed
  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. Pubmed
  9. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

2. Apoptosis regulator Bcl-2

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: activator

Components

Name UniProt ID Details
Apoptosis regulator Bcl-2 P10415 Details

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. Pubmed
  2. Akao Y, Maruyama W, Yi H, Shamoto-Nagai M, Youdim MB, Naoi M: An anti-Parkinson’s disease drug, N-propargyl-1®-aminoindan (rasagiline), enhances expression of anti-apoptotic bcl-2 in human dopaminergic SH-SY5Y cells. Neurosci Lett. 2002 Jun 28;326(2):105-8. Pubmed
  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. Pubmed
  4. Youdim MB, Amit T, Falach-Yogev M, Am OB, 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. Pubmed
  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. Pubmed

Enzymes

1. Cytochrome P450 1A2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 1A2 P05177 Details

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. Pubmed
  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. Pubmed
  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. Pubmed
  4. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:14