Description
Rasagiline mesylate is a potent and selective irreversible
monoamine oxidase B (MAO-B) inhibitor launched in 2005
in Israel by Teva as monotherapy in patients with early Parkinson's
disease and as adjuvant treatment in moderate-toadvanced
disease. Lundbeck will market the drug
throughout Europe. Rasagiline is in phase II clinical trials at
Teva and Eisai for the treatment of Alzheimer's type dementia.
Chemical Properties
White to Off-White Crystalline Solid
Uses
Rasagiline is a selective irreversible MAO-B inhibitor. Rasagiline is an Antiparkinsonian agent.
Uses
A selective irreversible MAO-B inhibitor. Antiparkinsonian
Uses
Rasagiline Mesylate is a new MAO-B inhibitor for the treatment of idiopathic Parkinson's disease.
Indications
Rasagiline mesylate is a novel, potent, second-generation, selective, irreversible MAO-B inhibitor that blocks the breakdown of dopamine. It is approved for the treatment of PD. Indications for use of once-daily rasagiline are as a monotherapy in early PD and as an adjunct to levodopa in moderate to advanced disease. Rasagiline significantly improves symptoms during initial monotherapy in patients with early PD and as an adjunct treatment to levodopa in moderate-to-advanced patients. Rasagiline is well tolerated up to doses as high as 20 mg/day. Evidence for neuroprotective effect of rasagiline is as follows (Jain 2010c):
Structure activity studies have shown that the neuroprotective activity is associated with the propargyl moiety of rasagiline, which protects mitochondrial viability.
Experimental evidence supports rasagiline's neuroprotective efficacy, showing that neuronal survival is related to the anti-apoptotic properties of its propargyl moiety.
Aminoindan metabolite of rasagiline has been shown to have neuroprotective properties (Bar-Am et al. 2010).
brand name
Azilect (Teva).
General Description
Rasagiline mesylate, (R)-N-(prop-2-ynyl)-2,3-dihydro-1H-inden-1-amine methanesulfonate(Azilect), belongs to the propargylamine family and is a whiteto off-white powder, soluble in water or ethanol, slightly solublein isopropanol. Rasagiline is rapidly absorbed. Plasmaprotein binding for rasagiline ranges from 88% to 94%, withspecific binding to serum albumin being 61% to 63%. It undergoescomplete biotransformation before excretion, mainlyvia N-dealkylation and hydroxylation, to yield three majormetabolites: 1(R)-aminoindan, 3-hydroxy-N-propargyl-1-aminoindan, and 3-hydroxy-1-aminoindan. Both oxidativepathways are catalyzed by cytochrome P450 (CYP) enzymes,mainly the 1A2 isozyme. Rasagiline and its metabolites undergoglucuronide conjugation with subsequent urinary excretion.Inhibitors of the CYP1A2 may increase plasmaconcentrations of rasagiline up to twofold. Because rasagilineis a selective and irreversible inhibitor of MAO-B, itsduration of action is independent of the drug’s half-life and isinstead determined by the regeneration rate of MAO-B. Thischaracteristic is potentially beneficial in PD, where rasagiline’sprolonged effect may be able to limit the fluctuating responsesthat are characteristic of long-term drug treatmentwith levodopa.
Biochem/physiol Actions
Rasagiline mesylate is an irreversible inhibitor of monoamine oxidase selective for MAO type B over type A by a factor of fourteen. It has anti-apoptotic and neuroprotectant activity and has been used as a treatment for Parkinson′s disease.
Mechanism of action
The specific mechanism of action of Rasagiline mesylate is unknown. One of these mechanisms is thought to be related to its MAO-B inhibitory activity, which leads to elevated extracellular dopamine levels in the striatum. It irreversibly blocks dopamine metabolism, thereby increasing dopamine levels, which can be beneficial for symptoms in Parkinson's disease patients.
Side effects
Rasagiline mesylate has been shown to be effective, safe and well tolerated as monotherapy in early Parkinson's disease. The most common are infection, headache, dizziness, weakness, anorexia and vomiting. In rare patients, it may cause new malignancies (melanoma and squamous cell carcinoma of the skin).
Synthesis
1-Indanone (122) was condensed with benzyl amine to give corresponding enamine which was reduced
with sodium borohydride in ethanol to give racemic Nbenzyl-
1-inda-namine (123) in 82% yield. The racemic
benzylamine 123 was resolved with L-tartaric acid and recrystallized
from boiling water to give optical pure Rbenzylamine
124 as a tartarate salt. The recovered S-isomer
125 can be racemized under basic condition to give back as
the starting racemic 123. Compound 124 was hydrogenated
and basified to give free amine 126 in 72 % yield which was
alkylated with propargyl chloride and K2CO3 in hot acetonitrile
to yield free resagiline. Finally resagiline mesilate
(XVII) was obtained by treating resagiline with methanesulfonic
acid in refluxing IPA.
storage
room temperature (desiccate)
References
1) Youdim?et al.?(2001),?Rasagiline [N-propargyl-1R(+)-aminoindan], a selective and potent inhibitor of mitochondrial monoamine oxidase B; Br. J. Pharmacol.,?132?500
2) Cereda?et al.?(2017),?Efficacy of rasagiline and selegiline in Parkinson’s disease: a head-to-head 3-year retrospective case-control study; J. Neurol.,?264?1254
3) Cronin and Grealy (2017),?Neuroprotective and Neuro-restorative Effects of Minocycline and Rasagiline in Zebrafish 6-Hydroxydopamine Model of Parkinson’s Disease; Neuroscience,?367?34
4) Kang?et al.?(2017),?TrkB neurotrophic activities are blocked by α-synuclein, triggering dopaminergic cell death in Parkinson’s disease; Proc. Natl. Acad. Sci. USA,?114?10773
5) Ledreux?et al.?(2016),?BDNF levels are increased by aminoindan and rasagiline in a double lesion model of Parkinson’s disease; Brain Res.,?1631?34
