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| Clinical data | |
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| Trade names | Azilect, others |
| Other names | TVP-1012; TVP1012;R(+)-AGN-1135;N-Propargyl-(R)-1-aminoindan;N-Propargyl-1(R)-aminoindan; (R)-PAI |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a606017 |
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| Routes of administration | By mouth[1][2] |
| Drug class | Monoamine oxidase inhibitor;Antiparkinsonian |
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| Pharmacokinetic data | |
| Bioavailability | 36%[2] |
| Protein binding | 88–94%[2] |
| Metabolism | Liver (CYP1A2)[2] |
| Metabolites | •(R)-1-Aminoindan[2] •3-OH-PAI[2] •3-OH-AI[2] |
| Eliminationhalf-life | 3 hours[2] |
| Excretion | Urine: 62%[2] Feces: 7%[2] |
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| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.301.709 |
| Chemical and physical data | |
| Formula | C12H13N |
| Molar mass | 171.243 g·mol−1 |
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Rasagiline, sold under the brand nameAzilect among others, is amedication which is used in the treatment ofParkinson's disease.[2][6] It is used as amonotherapy to treat symptoms in early Parkinson's disease or as anadjunct therapy in more advanced cases.[7] The drug is takenby mouth.[2]
Side effects of rasagiline includeinsomnia andorthostatic hypotension, among others.[2] Rasagiline acts as aninhibitor of theenzymemonoamine oxidase (MAO) and hence is amonoamine oxidase inhibitor (MAOI).[2] More specifically, it is aselective inhibitor ofmonoamine oxidase B (MAO-B).[2] The drug is thought to work by increasing levels of themonoamine neurotransmitterdopamine in thebrain.[2] Rasagiline showspharmacological differences from the related drugselegiline, including having noamphetamine-likemetabolites,monoamine-releasing activity, ormonoaminergic activity enhancer actions, which may result in clinical differences between the medications.[8][9]
Rasagiline was approved for medical use in theEuropean Union in 2005[10] and in theUnited States in 2006.[2][11]Generic versions of rasagiline are available.[12][13][14]
Rasagiline is used to treat symptoms ofParkinson's disease both alone and in combination with other drugs. It has shown efficacy in both early and advanced Parkinson's, and appears to be especially useful in dealing withnon-motor symptoms likefatigue.[15][16][2]
Teva conducted clinical trials attempting to prove that rasagiline did not just treat symptoms, but was adisease-modifying drug—that it actually prevented the death of the dopaminergic neurons that characterize Parkinson's disease and slowed disease progression. They conducted two clinical trials, called TEMPO and ADAGIO, to try to prove this. The United StatesFood and Drug Administration (FDA) advisory committee rejected their claim in 2011, saying that the clinical trial results did not prove that rasagiline was neuroprotective. The main reason was that in one of the trials, the lower dose (1 mg) was effective at slowing progression, but the higher dose (2 mg) was not, contradicting standarddose-response pharmacology.[17][18]
MAO-B inhibitors like rasagiline may improve certain non-motor symptoms in Parkinson's disease.[19] These may includedepression,sleep disturbances, andpain (particularly related to motor fluctuations), but are unlikely to includecognitive orolfactory dysfunctions.[19] The effects of MAO-B inhibitors like rasagiline onfatigue,autonomic dysfunctions,apathy, andimpulse control disorders in people with Parkinson's disease remain unknown.[19] Rasagiline has been reported to significantly improvequality of life in people with Parkinson's disease, but theeffect sizes were trivial to small and may not be clinically meaningful.[19] It showed a large effect size relative toplacebo for depression in people with Parkinson's disease.[19] In other studies, rasagiline appeared to reducefatigue in people with Parkinson's disease.[19][20][21][22] However, its effect sizes for this effect in a large trial were described as trivial.[19]
Rasagiline is available in the form of 0.5 and 1 mgoraltablets.[2][12]
Rasagiline has not been tested inpregnant women.[2]
The FDA label contains warnings that rasagiline may cause severehypertension orhypotension, maymake people sleepy, may make motor control worse in some people, may causehallucinations andpsychotic-like behavior, may causeimpulse control disorders, may increase the risk ofmelanoma, and uponwithdrawal, may cause highfever orconfusion.[2]
Side effects when the drug is taken alone includeflu-like symptoms,joint pain,depression,stomach upset,headache,dizziness, andinsomnia.[2] When taken withlevodopa, side effects include increasedmovement problems,accidental injury,sudden drops in blood pressure,joint pain andswelling,dry mouth,rash,abnormal dreams anddigestive problems includingvomiting,loss of appetite,weight loss,abdominal pain,nausea, andconstipation.[2] When taken with Parkinson's drugs other than levodopa, side effects include peripheral edema, fall, joint pain, cough, and insomnia.[2]
In a 2013meta-analysis, none of the most frequently reported side effects of rasagiline occurred significantly more often than withplacebo.[23] It was concluded that rasagiline iswell-tolerated.[23]
Rasagiline has been found to produceorthostatic hypotension as a side effect.[2] Rates of orthostatic hypotension in a selection of differentclinical trials have been 1.2- to 5-fold higher than those of placebo, ranging from 3.1 to 44% with rasagiline and 0.6 to 33% with placebo.[2][note 1] Orthostatic hypotension tends to be worst in the first 2 months of treatment and then tends to decrease with time.[2] Rasagiline can also causehypotension whilesupine and unrelated to standing.[2] In a clinical trial, the rate of hypotension was 3.2% with rasagiline versus 1.3% with placebo.[2]
Rarely, rasagiline has been reported to induceimpulse control disorders,[24][25][26][27][28]obsessive–compulsive symptoms,[29]hypersexuality,[30][31][32][27] andspontaneous orgasm orejaculation.[33][34][35][36] Other rare adverse effects associated with rasagiline includepleurothotonus (Pisa syndrome),[37][38][39]livedo reticularis,[40]tendon rupture,[41] andhypoglycemia.[42]
Serotonin syndrome has been reported rarely with rasagiline both alone and in combination withselective serotonin reuptake inhibitors (SSRIs) likeescitalopram,paroxetine, andsertraline and other MAOIs likelinezolid.[43][44][45][46][47][48][49][50]
Awithdrawal syndrome associated with rasagiline has been reported.[51]
Rasagiline has been studied at single doses of up to 20 mg and at repeated doses of up to 10 mg/day and was well-tolerated at these doses.[52][53][54] However, in adose-escalation study with concomitantlevodopa therapy, a dosage of 10 mg/day rasagiline was associated withcardiovascular side effects includinghypertension andorthostatic hypotension in some people.[2] The symptoms of rasagilineoverdose may be similar to the case of non-selective MAOIs.[2] Onset of symptoms may be delayed by 12 hours and may not peak for 24 hours.[2] A variety of different symptoms may occur and thecentral nervous system andcardiovascular system are prominently involved.[2] Death may result and immediate hospitalization is warranted.[2]Serotonin syndrome has occurred with rasagiline overdose andbody temperature should be monitored closely.[2] There is no specificantidote for overdose and treatment is supportive and based on symptoms.[2]
Rasagiline iscontraindicated with knownserotonergic agents likeselective serotonin reuptake inhibitors (SSRIs),serotonin–norepinephrine reuptake inhibitors (SNRIs),tricyclic antidepressants (TCAs),tetracyclic antidepressants (TeCAs),triazolopyridines orserotonin antagonists and reuptake inhibitors (SARIs) liketrazodone, and othermonoamine oxidase inhibitors (MAOIs), as well asmeperidine (pethidine),tramadol,methadone,propoxyphene,dextromethorphan,St. John's wort, andcyclobenzaprine, due to potential risk ofserotonin syndrome.[1][2] However, the risk appears to be low, based on a large study of 1,504 people which looked for serotonin syndrome in people with Parkinson's disease who were treated with rasagiline plus antidepressants, rasagiline without antidepressants, or antidepressants plus Parkinson's drugs other than either rasagiline or selegiline, and in which no cases were identified.[15]
There is a risk ofpsychosis or bizarre behavior if rasagiline is used with dextromethorphan.[2]
There is a risk of non-selective MAO inhibition and hypertensive crisis if rasagiline is used with other MAOIs.[2]
Rasagiline may have a risk ofhypertensive crisis in combination withsympathomimetic agents such asamphetamines,ephedrine,epinephrine,isometheptene, andpseudoephedrine.[1] However, based on widespread clinical experience with the related selective MAO-B inhibitorselegiline, occasional use ofover-the-counter sympathomimetics like pseudoephedrine appears to pose minimal risk of hypertensive crisis.[1] In any case, the combination of sympathomimetics with MAO-B inhibitors like rasagiline and selegiline should be undertaken with caution.[1]
Parkinson's disease is characterized by the death of cells that producedopamine, aneurotransmitter. An enzyme calledmonoamine oxidase (MAO) breaks down neurotransmitters. MAO has two forms,MAO-A andMAO-B. MAO-B is involved in the metabolism ofdopamine. Rasagiline prevents the breakdown of dopamine by irreversibly binding to MAO-B. Dopamine is therefore more available, somewhat compensating for the diminished quantities made in the brains of people with Parkinson's disease.[15]
Rasagiline acts as aselective andpotentirreversible inhibitor of themonoamine oxidases (MAO)enzymesmonoamine oxidase B (MAO-B) andmonoamine oxidase A (MAO-A).[2] It is selective for inhibition of MAO-B over MAO-A, but can also inhibit MAO-A at high doses or concentrations.[1][2] MAO-B is involved in themetabolism of themonoamine neurotransmitterdopamine in the body and brain.[1][2] By inhibiting MAO-B, rasagiline is thought to increase dopamine levels.[1][2] In the case ofParkinson's disease, increased dopamine levels in thestriatum are thought to be responsible for rasagiline's therapeutic effectiveness in treating the condition.[1][2]
Rasagiline inhibits platelet MAO-B activity with single doses by 35% one-hour after 1 mg, 55% after 2 mg, 79% after 5 mg, and 99% after 10 mg in healthy young people.[1][55][2][54] With all dose levels, maximum inhibition is maintained for at least 48 hours after the dose.[1][54] With repeated doses, rasagiline reaches greater than 99% platelet MAO-B inhibition after 6 days of 2 mg/day, 3 days of 5 mg/day, and 2 days of 10 mg/day.[1][55][54] Similarly, repeated administration of 0.5, 1, and 2 mg/day rasagiline resulted in complete MAO-B inhibition.[2] Clinically relevant inhibition of MAO-B is thought to require 80% inhibition and above.[1] Following the last dose, platelet MAO-B levels remain significantly inhibited for 7 days and return to baseline after 2 weeks.[1][54] In people with Parkinson's disease, rasagiline at a dose of 1 mg/day achieved near-complete inhibition of platelet MAO-B after 3 days of dosing.[1] The recommended dosing schedule of rasagiline in Parkinson's disease (1 mg/day) has been described as somewhat questionable and potentially excessive from a pharmacological standpoint.[56]
The half-time for recovery of brain MAO-B following discontinuation of an MAO-B inhibitor (specifically selegiline) has been found to be approximately 40 days.[1] Similarly, recovery of brain MAO-B following rasagiline discontinuation was gradual and occurred over 6 weeks.[57][58] The clinical effectiveness of rasagiline in Parkinson's disease has been found to persist during a 6-week washout phase with discontinuation of the medication.[1]
Rasagiline is about 30 to 100 times more potent in inhibiting MAO-B than MAO-Ain vitro and is about 17 to 65 times more potent in inhibiting MAO-B over MAO-Ain vivo in rodents.[1] Rasagiline does not importantly potentiate thepressor effects oftyramine challenge in humans, indicating that it is selective for MAO-B inhibition and does not meaningfully inhibit MAO-A.[1][2] It is expected that at sufficiently high doses rasagiline would eventually become non-selective and additionally inhibit MAO-A in humans.[1][2] However, it is unknown what dose threshold would be required for this to occur.[1]
Rasagiline is theR(+)-enantiomer of AGN-1135, aracemic mixture of rasagiline (TVP-1012) and theS(–)-enantiomer (TVP-1022).[55][1] Virtually all of the MAO-inhibiting activity of AGN-1135 lies in theR(+)-enantiomer rasagiline, with this enantiomer having 1,000-fold greater inhibitory potency of MAO-B than theS(–)-enantiomer.[55][1] In addition, theS(–)-enantiomer is poorly selective for MAO-B over MAO-A.[1] As a result, the purifiedR(+)-enantiomer rasagiline was the form of the compound advanced for clinical development.[55][1]
Selegiline was the first selective MAO-B inhibitor.[59] Selegiline and rasagiline have similarselectivity for inhibition of MAO-B over MAO-A.[8][60] However, rasagiline is 5- to 10-fold more potent than selegiline at inhibiting MAO-B, which results in the former being used at lower doses clinically than the latter (1 mg/day versus 5–10 mg/day, respectively).[8][1][60] In addition, selegiline ismetabolized intolevomethamphetamine andlevoamphetamine.[61] These metabolitesinduce the release of norepinephrine and dopamine, havesympathomimetic andpsychostimulant effects, and may contribute to the effects andside effects of selegiline.[8][62] In contrast to selegiline, rasagiline does not convert intometabolites with amphetamine-like effects.[1] The amphetamine metabolites of selegiline may contribute to significant clinical differences between selegiline and rasagiline.[8]
Rasagiline metabolizes into(R)-1-aminoindan which has no amphetamine-like effects and shows neuroprotective properties in cells and in animal models.[10]
Selective MAO-B inhibitors including rasagiline and selegiline have been found to increase dopamine levels in the striatum in ratsin vivo.[63][64][65] It has been theorized that this might be due to strong inhibition of the metabolism ofβ-phenylethylamine, which is anendogenous MAO-B substrate that hasmonoaminergic activity enhancer andnorepinephrine–dopamine releasing agent actions.[63][64][65][66][67] β-Phenylethylamine has been described as "endogenous amphetamine" and its brain levels are dramatically increased (10- to 30-fold) by MAO-B inhibitors like selegiline.[68][69][67] Elevation of β-phenylethylamine may be involved in the effects of MAO-B inhibitors in the treatment of Parkinson's disease.[63][64][65][67]
In 2021, it was discovered that MAO-A is solely or almost entirely responsible for striatal dopaminecatabolism in the rodent brain and that MAO-B is not importantly involved.[70][71][72] In contrast, MAO-B appears to mediatetonicγ-aminobutyric acid (GABA) synthesis fromputrescine in the striatum, a minor and alternativemetabolic pathway of GABA synthesis, and this synthesized GABA in turn inhibits dopaminergic neurons in this brain area.[70][71][72][73] MAO-B specifically mediates thetransformations of putrescine intoγ-aminobutyraldehyde (GABAL or GABA aldehyde) andN-acetylputrescine intoN-acetyl-γ-aminobutyraldehyde (N-acetyl-GABAL orN-acetyl-GABA aldehyde),metabolic products that can then be converted into GABA viaaldehyde dehydrogenase (ALDH) (and an unknowndeacetylaseenzyme in the case ofN-acetyl-GABAL).[73][74][71][72] These findings may warrant a rethinking of the pharmacological actions of MAO-B inhibitors like selegiline and rasagiline in the treatment of Parkinson's disease.[70][71][72]
Rasagiline is selective for inhibition of MAOs over interactions with otherproteins, includingα-adrenergic receptors,β-adrenergic receptors,muscarinic acetylcholine receptors, and othertargets.[1][60]
The major metabolite of rasagiline,(R)-1-aminoindan, is either devoid of MAO inhibition or shows only weak inhibition of MAO-B.[1][56] It also has noamphetamine-like activity.[1][56] However,1-aminoindan is not lacking in pharmacological activity.[1][56] Like rasagiline, 1-aminoindan showsneuroprotective activity in some experimental models.[1][56] In addition, 1-aminoindan has been found to enhancestriataldopaminergicneurotransmission and improvemotor function independent of MAO inhibition inanimal models of Parkinson's disease.[56]
2-Aminoindan, a closely relatedpositional isomer of 1-aminoindan, is known toinhibit the reuptake andinduce the release of dopamine and norepinephrine and to producepsychostimulant-like effects in rodents, albeit with lowerpotency thanamphetamine, but rasagiline does not metabolize into this compound.[75][76] 1-Aminoindan has been found to inhibit the reuptake of norepinephrine 28-fold less potently than 2-aminoindan and to inhibit the reuptake of dopamine 300-fold less potently than 2-aminoindan, withIC50Tooltip half maximal inhibitory concentration values for dopamine reuptake inhibition in one study of 0.4 μM foramphetamine, 3.3 μM for 2-aminoindan, and 1 mM for 1-aminoindan.[76][77][78] In contrast to 2-aminoindan, whichincreased locomotor activity in rodents (+49%), 1-aminoindansuppressed locomotor activity (–69%).[76] On the other hand, 1-aminoindan has been found to enhance the psychostimulant-like effects of amphetamine in rodents.[77]
Whereas selegiline is acatecholaminergic activity enhancer, which may be mediated byagonism of theTAAR1, rasagiline does not possess this action.[66][79][9][80] Instead, rasagiline actually antagonizes selegiline's effects as a catecholaminergic activity enhancer, which may be mediated by TAAR1antagonism.[9]
Rasagiline has been reported to directly bind to andinhibitglyceraldehyde-3-phosphate dehydrogenase (GAPDH).[8][81] This might play a modulating role in its clinical effectiveness for Parkinson's disease.[8][81] Selegiline also binds to and inhibits GAPDH.[8]
Rasagiline has been found to bindreversibly toα-synuclein, a majorprotein involved in thepathophysiology of Parkinson's disease, and this action might beneuroprotective.[82][83][84]
Rasagiline is rapidlyabsorbed from thegastrointestinal tract withoral administration and has approximately 36%absolute bioavailability.[1][2] Thepeak andarea-under-the-curve levels of rasagiline arelinear and dose-proportional over a dose range of 0.5 to 10 mg.[1][2] Thetime to peak levels of rasagiline is 0.5 to 0.7 hours andsteady-state peak levels are on average 8.5 ng/mL.[1][2]
At steady-state, the time to peak levels of rasagiline's major metabolite(R)-1-aminoindan is 2.1 hours, its peak levels are 2.6 ng/mL, and its area-under-the-curve levels are 10.1 ng/h/mL.[1]
Taking rasagiline withfood (as a high-fat meal) increases peak levels by approximately 60% and area-under-the-curve levels by approximately 20%, whereas time to peak levels is unchanged.[1][2] Because exposure to rasagiline is not substantially modified, rasagiline can be taken with or without food.[1][2]
The meanvolume of distribution of rasagiline is 87 L or 182 to 243 L depending on the source.[1][2] It readily crosses theblood–brain barrier and enters thecentral nervous system.[1]
Theplasma protein binding of rasagiline is 60 to 70% or 88 to 94% depending on the source.[1][2] In the case of the latter range, 61 to 63% of binding was toalbumin.[2]
Rasagiline is extensivelymetabolized in theliver.[1][2] It is metabolized primarily by hepaticN-dealkylation via thecytochrome P450enzymeCYP1A2 which forms the majormetabolite(R)-1-aminoindan.[1][2][53] It is also metabolized byhydroxylation via cytochrome P450 enzymes to form 3-hydroxy-N-propargyl-1-aminoindan (3-OH-PAI) and 3-hydroxy-1-aminoindan (3-OH-AI).[2] Rasagiline and its metabolites also undergoconjugation viaglucuronidation.[2]
Use of rasagiline should be monitored carefully in people taking other drugs thatinhibit orinduce CYP1A2.[2][85] Variants in CYP1A2 have been found to modify exposure to rasagiline in some studies but not others.[85][86]Tobacco smoking, a known inhibitor of CYP1A2, did not modify rasagiline exposure.[85]Drug transporters may be more important in influencing the pharmacokinetics of rasagiline than metabolizing enzymes.[86]
Exposure to rasagiline is increased in people withhepatic impairment.[1][2] In those with mild hepatic impairment, peak levels of rasagiline are increased by 38% and area-under-the-curve levels by 80%, whereas in people with moderate hepatic impairment, peak levels are increased by 83% and area-under-the-curve levels by 568%.[1][2] As a result, the dosage of rasagiline should be halved to 0.5 mg/day in people with mild hepatic impairment and rasagiline is considered to becontraindicated in people with moderate to severe hepatic impairment.[2]
Rasagiline iseliminated primarily inurine (62%) and to a much lesser extent infeces (7%).[2]Rasagiline isexcreted unchanged in urine at an amount of less than 1%.[1] Hence, it is almost completely metabolized prior to excretion.[2]
Theelimination half-life of rasagiline is 1.34 hours.[1] Atsteady-state, its half-life is 3 hours.[2] As rasagiline acts as anirreversible inhibitor of MAO-B, its actions andduration of effect are not dependent on its half-life or sustained concentrations in the body.[1][2]
The oralclearance of rasagiline is 94.3 L/h and is similar to normal liver blood flow (90 L/h).[1] This indicates that non-hepatic mechanisms are not significantly involved in the elimination of rasagiline.[1]
Moderaterenal impairment did not modify exposure to rasagiline, whereas that of(R)-1-aminoindan was increased by 1.5-fold.[2] Since (R)-1-aminoindan is not an MAO inhibitor, mild to moderate renal impairment does not require dosage adjustment of rasagiline.[2] No data are available in the case of severe or end-stage renal impairment.[2]
Rasagiline, also known as (R)-N-propargyl-1-aminoindan and by its former developmental code name TVP-1012, is asecondarycyclicbenzylaminepropargylamine.[1][55] It is theR(+)-enantiomer of thechiralracemiccompound AGN-1135 (N-propargyl-1-aminoindan), whereas theS(–)-enantiomer is TVP-1022 ((S)-N-propargyl-1-aminoindan).[1][55] Rasagiline is apotent andselectiveMAO-Binhibitor, whereas TVP-1022 is a very weak and poorly selective MAO inhibitor.[1][55]
Both thehydrochloride andmesylatesalts of rasagiline were studied and were found to have similarpharmacological,pharmacokinetic, andtoxicological profiles.[1] However, the mesylate salt of rasagiline was ultimately selected for its use as apharmaceutical drug due to favorablechemical stability.[1][2]
The propargylmoiety is essential in thepharmacodynamics of rasagiline.[1] It bindscovalently andirreversibly with theflavin adenine dinucleotide (FAD) moiety of the MAOenzyme.[1] Theselectivity of rasagiline forMAO-B overMAO-A depends on the maintenance of a distance of no more than twocarbon atoms between thearomatic ring and theN-propargyl group.[1] The propargyl group of rasagiline is also essential for itsneuroprotective andantiapoptopic actions, which are independent of its MAO inhibition.[1]
Rasagiline is closely structurally related toselegiline (R(–)-N-propargylmethamphetamine).[1] However, in contrast to selegiline, rasagiline is not asubstituted amphetamine and is instead an1-aminoindanderivative.[1] Thechemical structures of the amphetamines andaminoindans are very similar.[87] However, whereas selegilinemetabolizes intolevomethamphetamine andlevoamphetamine and can produceamphetamine-like effects, rasagiline does not do so.[1][75] Instead, it metabolizes into(R)-1-aminoindan (TVP-136) and has no such actions.[1][75][88][89]
SU-11739 (AGN-1133;N-methyl-N-propargyl-1-aminoindan), theN-methylatedanalogue of rasagiline, is also an MAO-B-preferring MAOI.[55][90][91] However, it is less selective for inhibition of MAO-B over MAO-A than rasagiline.[90][91] Another structurally related selective MAO-B inhibitor,ladostigil (N-propargyl-(3R)-aminoindan-5-yl-N-propylcarbamate; TV-3326), was developed fromstructural modification of rasagiline and additionally acts as anacetylcholinesterase inhibitor due to itscarbamate moiety.[1]
Rasagiline and its metabolite (R)-1-aminoindan arestructurally related to2-aminoindan andderivatives like5,6-methylenedioxy-2-aminoindane (MDAI),5,6-methylenedioxy-N-methyl-2-aminoindane (MDMAI), and5-iodo-2-aminoindane (5-IAI).[75]
AGN-1135, the racemic form of the drug, was invented by Aspro Nicholas in the early 1970s.Moussa B. H. Youdim identified it as a potential drug for Parkinson's disease, and working with collaborators at Technion – Israel Institute of Technology in Israel and the drug company,Teva Pharmaceuticals, identified the R-isomer as the active form of the drug.[92] Teva brought it to market in partnership withLundbeck in the European Union andEisai in the United States and elsewhere.
Prior to the discovery of rasagiline, a closely relatedanalogue calledSU-11739 (AGN-1133; J-508;N-methyl-N-propargyl-1-aminoindan) waspatented in 1965.[93] At first, theN-methyl was necessary for the agent to be considered a ring cyclized analogue ofpargyline with about 20 times the potency.[94] However, theN-methyl compound was a non-selective MAOI.[91] In addition, SU-11739 has been reported to have strongcatecholamine-releasing actions.[95]
Racemic rasagiline was discovered and patented by Aspro Nicholas in the 1970s as a drug candidate for treatment ofhypertension.[96]
Moussa B. H. Youdim was involved in developingselegiline as a drug for Parkinson's, in collaboration with Peter Reiderer.[97] He called the compound AGN 1135.[98] In 1996 Youdim, in collaboration with scientists from Technion and the USNational Institutes of Health, and using compounds developed withTeva Pharmaceuticals, published a paper in which the authors wrote that they were inspired by the racemic nature of deprenyl and the greater activity of one of its stereoisomers, L-deprenyl, which becameselegiline, to explore the qualities of the isomers of the Aspro compound, and they found that the R-isomer had almost all the activity; this is the compound that became rasagiline.[98] They called the mesylate salt of the R-isomer TVP-1012 and the hydrochloride salt, TVP-101.[98]
Teva and Technion filed patent applications for this racemically pure compound, methods to make it, and methods to use it to treat Parkinson's disease and other disorders, and Technion eventually assigned its rights to Teva.[96]
Teva begandevelopment of rasagiline, and by 1999 was in Phase III trials, and entered into a partnership withLundbeck in which Lundbeck agreed to share the costs and obtained the joint right to market the drug in the European Union.[99] In 2003, Teva partnered withEisai, giving Eisai the right to jointly market the drug for Parkinson's in the US, and to co-develop and co-market the drug forAlzheimer's disease and other neurological diseases.[100]
It was approved by theEuropean Medicines Agency for Parkinson's in 2005[10] and in the United States in 2006.[11]
Following its approval, rasagiline was described by some authors as a "me-too drug" that offered nothing new in terms of effectiveness and tolerability compared to selegiline.[101][102] However, others have contended that rasagiline shows significant differences from and improvements over selegiline, like its lack ofamphetaminemetabolites and associatedmonoamine releasing agent effects, which may improvetolerability andsafety.[101][8] Conversely, others have maintained that rasagiline may be less efficacious than selegiline due to its lack ofcatecholaminergic activity enhancer actions.[66][9][103][104]
Rasagiline is thegeneric name of the drug and itsINNTooltip International Nonproprietary Name andUSANTooltip United States Adopted Name.[105][106] It is also known by its former developmental code nameTVP-1012.[55] Rasagiline is marketed under the brand name Azilect, among others.[2][12]
Lower-costgeneric versions of rasagiline are available.[12][13][14]
Rasagiline was under development for the treatment ofAlzheimer's disease.[107] However, development was discontinued.[107]
Rasagiline was tested for efficacy in people withmultiple system atrophy in a large randomized, placebo-controlled, double-blinddisease-modification trial; the drug failed.[16][108]
Rasagiline has been reported to improve symptoms in people withfreezing gait.[109][110]
Rasagiline has been studied in the treatment ofamyotrophic lateral sclerosis (ALS; Lou Gehrig's disease).[111][112][113][114]
Rasagiline has been described as an emerging potentialantidepressant.[115] MAO-B inhibitors have been found to reduce depressive symptoms in people with Parkinson's disease with a smalleffect size.[116][19] However, rasagiline does not appear to have been studied in the treatment of depression in people without Parkinson's disease[117] and it has not been developed nor approved for the treatment depression.[107] In ananimal study,selegiline was effective inmodels ofantidepressant-like activity, whereas rasagiline was ineffective.[118][119] The antidepressant effects of selegiline in animals appear to be independent of monoamine oxidase inhibition and may be related to itscatecholaminergic activity enhancer (CAE) activity, which rasagiline lacks.[118][119]
Rasagiline has not been studied in the treatment ofpsychostimulant addiction as of 2015.[120]
Rasagiline has been reported to improverestless legs syndrome (RLS).[121][122][123]
{{cite book}}:|journal= ignored (help)2-AI selectively inhibited just NET, and for SERT and DAT it has low potency. Apart from inhibitory actions on transporter molecules, aminoindanes have been shown to cause transporter-mediated release (reverse transport) of monoamines: MDAI released 5-HT and NE, 5-IAI released 5-HT and DA, and 2-AI released NE and DA (33).
{{cite book}}:|journal= ignored (help)In addition, the compounds previously described by Knoll and colleagues [33, 34], along with a series of trace amine derivatives synthesized by Ling et al. [35] are potential TAAR ligands. Although neither of these classes of compound appear to have been examined for efficacy at TAAR, their strong structural similarity to trace amines suggests that such studies are warranted.
{{cite journal}}: CS1 maint: DOI inactive as of July 2025 (link){{cite book}}:|journal= ignored (help)The precise mechanism behind the enhancer activity is not yet clarified. Recent data demonstrated, that antidepressant effect of DEP, or its action on the hippocampal long-term potentiation is independent from the MAO-B inhibition, as rasagiline, a potent MAO-B inhibitor was lack[ing] of these effects [36].
