136236-51-6 Usage
Description
Rasagiline is a second-generation, irreversible monoamine oxidase type B
(MAO-B) inhibitor that has been launched for the treatment of Parkinson’s disease
(PD). Unlike its predecessor selegiline, it is not metabolized to amphetamine
derivatives and is, therefore, devoid of the sympathomimetic activity responsible
for adverse side effects. Rasagiline is, however, similar to selegiline in the retention
of the propargylamine moiety; this essential pharmacophore binds covalently to
selectively form an irreversible bond with the flavin adenine dinucleotide portion of
the MAO-B enzyme. As an adjunct therapy, rasagiline treats the fluctuations in motor symptoms.
The R-enantiomer exhibits 4-times the potency of the S-enantiomer, so the
synthetic method begins with the optical resolution of racemic N-benzyl-1-aminoindan
using (R,R)-tartaric acid as the resolving agent. Once isolated, the
enantiomerically-enriched salt is submitted to hydrogenolysis to afford 1(R)-
aminoindane that is subsequently propargylated to provide rasagiline. It is formulated
as its mesylate salt, and the recommended dosage of rasagiline is 1 mg/day,
with or without levodopa. Entacapone, a catecholamine-
O-methyltransferase inhibitor known as an effective add-on therapy for motor
fluctuations, was used as a comparator. Rasagiline reduced the time spent in the
“off” state while increasing the “on” time.
Originator
Teva/Eisai/Lundbeck (Israel)
Characteristics
Rasagiline, [N-propargyl-1R(+)aminoindan] is a unique, selective, and potent secondgeneration mitochondrial monoamine oxidase B inhibitor with distinctive neuroprotective as well as therapeutic properties for the treatment of PD.
Uses
5HT4 receptor agonist, peristaltic stimulant. Rasagiline, is a selective and irreversible propargylamine inhibitor of monoamine oxidase which has been used to increase the availability of dopamine at striatal receptors as a method to treat Parkinson’s disease.
Definition
ChEBI: An indane that consists of 1-aminoindane bearing an N-propargyl substituent. A selective, irreversible monoamine oxidase-B inhibitor.
Indications
Rasagiline has a role in the treatment of PD by virtue of its proven ability to reduce the signs of PD in both the “on” and “off” states, and to improve global function. It appears to be of value in early stages of PD as well as after the appearance of clinical fluctuations in response to LD. Rasagiline also has a promising but not fully explored potential to halt or slow down the progression of PD, as well as other clinical conditions. The accumulating evidence of rasagiline’s neuroprotective effects in animal and cellular models is both intriguing and exciting. Further careful scientific basic and clinical studies and clinical experience are needed to establish the full therapeutic benefits of rasagiline for the treatment of PD.
Brand name
Azilect (Teva).
Mechanism of action
Rasagiline has many neuroprotective properties in animal and cell culture models of PD as well as a variety of other conditions that are too numerous to delineate completely, so only some of these studies are mentioned here.
Some studies suggest that the neuroprotective effects of rasagiline are potentially separate and unrelated to its therapeutic effects.For example, the S-enantiomer of rasagiline lacks the MAOB inhibitory and the antidepressant effects of rasagiline but shares with rasagiline its neuroprotective effects and its cholinesterase inhibitory effects.This suggests that the neuroprotective effects of rasagiline are independent of its antidepressant and MAOB inhibitory effects. Rasagiline protects dopaminergic SHSY5Y cells in culture by inhibiting mitochondrial permability transition, an apoptosis inducing effect, of an endogenous neurotoxin (N-methyl(R) salsolinol).In the same cell model, rasagiline also enhances the expression of the Bcl-2 gene family which have antiapoptotic effects.Finally, rasagiline prevents the apoptosis and nuclear accumulation of glyceraldehyde-3-phosphate dehydrogenase induced by N-methyl (R) salsonilol in human dopaminergic SH-SY5Y cell cultures.Since the SH-SY5Y cell system does not contain MAO, these protective effects must have other mechanisms. Rasagiline also is protective in vivo against MPTP (mice) and 6OHDA (rats) (see Reference 100). In primate models of PD, rasagiline led to a return toward normal of cognitive and motor function, even in the absence of LD.
In neuronal cell models (SH-SY5Y neuroblastoma cells and neuronally differentiated PC12 cells), rasagiline increases SOD activity and Bcl-2 expression, and it inhibits activation of capsase 3, prevents DNA laddering, inhibits toxin induced fall in mitochondrial membrane potential, prevents toxin induced apoptosis, and protects against cell death due to ischemia and glucose deprivation.Rasagiline also has protective effects against stroke occurrence and promotes survival in spontaneously hypertensive rats.
Pharmacokinetics
Rasagiline, or TV3326, or [N-propargyl-1R(+)ami-noindan], is a selective and highly potent second-generation mitochondrial monoamine oxidase B inhibitor.As opposed to selegiline, rasagiline has quite a different metabolite profile. Selegiline’s major metabolites are amphetamine and methamphetamine, while rasagiline’s primary metabolite is aminoindan. While amphetamine and methamphetamine are potently addictive substances, they may promote alertness. Aminoindan has beneficial effects of its own and has no known adverse side effects.In man, 1-mg daily dosages of rasagiline inhibit platelet MAO-B nearly completely.Rasagiline has both therapeutic and protective properties.
Clinical Use
Rasagiline [R(+)-N-propargyl-1-aminoindan] mesylate (Azilect?) was approved by the FDAin May of 2006 as monotherapy in early disease and as an adjunct to levodopa in more advanced disease. The recommended doses are 1 mg once a day in early disease and an initial dose of 0.5 mg once a day in advanced disease that can be increased to 1 mg once a day if needed. It produces selective irreversible MAO-B inhibition. Platelet MAO-B inhibition is dose-dependent; one hour after ingestion, platelet MAOB inhibition is 35% with 1 mg rasagiline and 99% with 10 mg rasagiline. By day 6, rasagiline 2 mg/day inhibits over 99% of platelet MAO-B. After discontinuing rasagiline, it takes approximately two weeks for MAO-B activity to return to baseline values. The area under the curve (AUC) and maximum concentration (Cmax) increase linearly with rasagiline dosage. The plasma half-lives of rasagiline and its active metabolite 1(R)-aminoindan are 3.5 hours and 11 hours, respectively. As rasagiline irreversibly inhibits MAO-B, the serum (pharmacokinetic) half-life does not correlate with its functional (pharmacodynamic) half-life.
Rasagiline up to 20 mg/day was well tolerated in healthy male volunteers. Dry mouth, headache, nausea, thirst, and abdominal discomfort were the most common adverse effects but tended to be mild. There were no significant effects on vital signs, lab values, physical exam, or EKG.
Drug interactions
Potentially hazardous interactions with other drugs
Analgesics: avoid with dextromethorphan; avoid
with pethidine (risk of serious adverse reactions) -
allow at least 14 days before starting pethidine.
Antidepressants: avoid with other MAOIs (can
lead to hypertensive crisis) - allow at least 14 days
before starting a MAOI; avoid with fluoxetine
and fluvoxamine; allow 5 weeks between stopping
fluoxetine and starting rasagiline; allow 14 days
between stopping rasagiline and starting fluoxetine
or fluvoxamine; increased CNS toxicity with SSRIs,
tricyclics and vortioxetine.
Sympathomimetics: concomitant use is not
recommended.
Metabolism
Rasagiline is extensively metabolised in the liver by
N-dealkylation and hydroxylation, via the cytochrome
P450 isoenzyme CYP1A2, and conjugation.
1-Aminoindan is a major metabolite and is stated to be
active although it is not a monoamine oxidase B inhibitor.
The metabolites are excreted mainly in the urine and
partly in the faeces.
Check Digit Verification of cas no
The CAS Registry Mumber 136236-51-6 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,3,6,2,3 and 6 respectively; the second part has 2 digits, 5 and 1 respectively.
Calculate Digit Verification of CAS Registry Number 136236-51:
(8*1)+(7*3)+(6*6)+(5*2)+(4*3)+(3*6)+(2*5)+(1*1)=116
116 % 10 = 6
So 136236-51-6 is a valid CAS Registry Number.
InChI:InChI=1/C12H11N/c1-2-9-13-12-8-7-10-5-3-4-6-11(10)12/h1,3-8,12-13H,9H2/t12-/m1/s1
136236-51-6Relevant articles and documents
A validated normal phase LC method for enantiomeric separation of rasagiline mesylate and its (S)-enantiomer on cellulose derivative-based chiral stationary phase
Sunil Reddy,Sudhakar Babu,Kumar, Navneet
, p. 324 - 327 (2013)
A simple, sensitive, and robust normal-phase isocratic HPLC-UV method was developed and validated for the enantiomeric separation of rasagiline mesylate and its (S)-enantiomer. The rasagiline and its (S)-enantiomer were resolved on a Chiralcel-OJ-H (4-methylbenzoate cellulose coated on silica) column using a mobile phase consisting of n-hexane:isopropyl alcohol:ethanol:diethyl amine (96:2:2:0.01) at a flow rate of 1.0 ml/min. The column temperature was maintained at 27 °C and elution was monitored at 215 nm. The resolution (Rs) between the enantiomers was found to be more than 2.0. The limit of detection and the limit of quantification of the (S)-enantiomer were found to be 0.35 and 1.05 μg/ml, respectively. The developed method was validated as per ICH guidelines with respect to linearity, limit of detection and quantification, accuracy, precision, and robustness - and satisfactory results were obtained. The sample solution and mobile phase were found to be stable up to 48 h. The method is useful for routine evaluation of the quality of rasagiline mesylate in bulk drug-manufacturing units.
Enantioselective synthesis of 1-aminoindene derivativesviaasymmetric Br?nsted acid catalysis
Ding, Du,Jiang, Hua-Jie,Wang, Tao,Wu, Xiang,Zhang, Ying,Zhao, Li-Ping
supporting information, p. 9680 - 9683 (2021/09/30)
We describe a catalytic asymmetric iminium ion cyclization reaction of simple 2-alkenylbenzaldimines using a BINOL-derived chiralN-triflyl phosphoramide. The corresponding 1-aminoindenes and tetracyclic 1-aminoindanes are formed in good yields and high enantioselectivities. Further, the chemical utility of the obtained enantiopure 1-aminoindene is demonstrated for the asymmetric synthesis of (S)-rasagiline.
CHIRAL CATALYST AND METHOD FOR ASYMMETRIC REDUCTION OF AN IMINE
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Paragraph 00179; 00180; 00181; 00182; 00183; 00184, (2019/04/16)
The present disclosure discusses (i) a compound having a chemical formula according to Formula (I), or its enantiomer; and (ii) a compound that is reactive with a hydride to produce a compound having a chemical formula according to Formula (I), or its enantiomer. Formula (I) is: Formula (I) where R1 and R2 are H, optionally substituted C1-C3 alkyl, or linked together to form an optionally substituted C3 or C4 alkyl group; R3 and R3' are H; R4 and R4' are the same, and are optionally substituted C1-C6 alkyl; and R5 and R5' are the same, and are optionally substituted aryl or heteroaryl. In some examples, R4 and R5 are linked, and R4' and R5' are linked, where both linking groups are the same. The present disclosure also discusses methods of asymmetric reduction of an imine, and methods of forming the catalysts and pre-catalysts.
Kinetic Resolution and Deracemization of Racemic Amines Using a Reductive Aminase
Aleku, Godwin A.,Mangas-Sanchez, Juan,Citoler, Joan,France, Scott P.,Montgomery, Sarah L.,Heath, Rachel S.,Thompson, Matthew P.,Turner, Nicholas J.
, p. 515 - 519 (2018/02/15)
The NADP(H)-dependent reductive aminase from Aspergillus oryzae (AspRedAm) was combined with an NADPH oxidase (NOX) to develop a redox system that recycles the co-factor. The AspRedAm-NOX system was applied initially for the kinetic resolution of a variety of racemic secondary and primary amines to yield S-configured amines with enantiomeric excess (ee) values up to 99 %. The addition of ammonia borane to this system enabled the efficient deracemization of racemic amines, including the pharmaceutical drug rasagiline and the natural product salsolidine, with conversions up to >98 % and >99 % ee Furthermore, by using the AspRedAm W210A variant it was possible to generate the opposite R enantiomers with efficiency comparable to, or even better than, the wildtype AspRedAm.
