Name | Rasagiline |
Synonyms | Rasagiline Unii-003N66ts6t Rasagiline -13C3 (R)-N-2-Propynyl-1-indanamine 1-Indanamine, N-2-propynyl-, (R)- (R)-N-(2-Propynyl)-2,3-dihydroinden-1-aMine (R)-2,3-DIHYDRO-N-2-PROPYNYL-1H-INDEN-1-AMINE 1H-Inden-1-amine, 2,3-dihydro-N-2-propynyl-, (1R) (1R)-N-prop-2-yn-1-yl-2,3-dihydro-1H-inden-1-amine |
CAS | 136236-51-6 |
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 |
Molecular Formula | C12H13N |
Molar Mass | 171.24 |
Density | 1.05±0.1 g/cm3(Predicted) |
Melting Point | 148 °C |
Boling Point | 305.5±30.0 °C(Predicted) |
Solubility | Dichloromethane |
Appearance | White to Brown Powder |
Color | Off-White to Light Beige to Orange Sticky to |
pKa | 6.95±0.20(Predicted) |
Storage Condition | under inert gas (nitrogen or Argon) at 2–8 °C |
Stability | Light Sensitive |
Refractive Index | 1.606 |
MDL | MFCD00866571 |
Parkinson's disease treatment drugs | Parkinson's disease (parkinson's disease,PD) is a common chronic degenerative disease of the nervous system. The disease can be found in all age groups, but most of them are middle-aged and elderly. With the aging of the population, its incidence rate is increasing year by year, and the affected population is showing a trend of youth, which has caused a heavy burden to the family and society. At present, levodopa (L-dopa) is still the most effective drug for the treatment of PD, but after 2 to 5 years of use, there will be reduced efficacy and long-term side effects, such as movement fluctuations (including end-of-dose phenomenon, switching phenomenon and freezing phenomenon) And dyskinesia (including bipolar dystonia and dystonia). Rasagiram (rasagiline, trade name Azilect) is a Parkinson's disease treatment drug. It is a Parkinson's disease (PD) treatment drug jointly developed by Lundbeck and Teva. It is a novel and effective second-generation selective monoamine oxidase B(MAO-B) inhibitor. The drug was first approved for listing in Israel in January 2005, then approved by the European Union in February 2005, and first listed in the EU country UK in June 2005, and has been approved by FDA. Rasagelan is an irreversible type B monoamine oxidase (MAO-B) selective inhibitor, which can inhibit dopamine degradation and increase dopamine accumulation. At the same time, it can reduce the reuptake of dopamine by presynaptic membrane, promote the release of dopamine, and improve the clinical symptoms of PD patients. It is 5 times more effective than selegilan in preventing tremor paralysis caused by 1 -methyl -4 -phenyl -1,2,3, 6-tetrahydropyridine (1 -methyl -4 -phenyl -1,2,3,6 -tetrahydropyridine,MPTP). The main metabolite of rasagiline, 1-(R)-aminoindan, is not addictive to the amphetamine class. In addition to inhibiting monoamine oxidase B, rasagiline can also prevent the opening of mitochondrial filter pores, reduce the release of cytochrome C, change anti-apoptosis genes and proteins, and inhibit the nuclear translocation of glyceraldehyde-3-phosphate dehydrogenase. Increase neurotrophic factor. In clinical studies, rasagline monotherapy has a mild effect and is an effective monotherapy or adjuvant levodopa therapy for early and late PD. Studies have confirmed that early use of rasagline is effective in the treatment of tremor paralysis and may delay the course of the disease. It has been widely used in clinical practice. |
Mechanism of action | Rasagiline is a selective and irreversible monoamine oxidase proparynylamine inhibitor, used to increase the striatal receptor dopamine Availability, as a treatment for Parkinson's disease method. The main chemical structure is N-propargyl-1-aminoindan, which is an irreversible MAO-B selective inhibitor, which can enhance the signal transmission of dopamine and block the decomposition of dopamine in the brain. At the same time, it can increase the extracellular level of dopamine in the striatum. The increased dopamine level and the subsequent increase of dopaminergic activity can regulate dopaminergic motor dysfunction. In addition, unlike other anti-PD drugs, rasagiline also has neuroprotective effects. Its S-isomer (TVP1022, MAO inhibitory activity is very weak) in the nerve cell culture test of various neurotoxins, both of which show neuroprotective effect, suggesting that rasagiline's inhibitory effect on MAO is not a necessary condition for neuroprotective effect, but may be related to the propargylamine (propargylamine) part of its structure, the latter protects the activity of mitochondria and the osmotic transport pore of mitochondria by activating the Bcl-2 and down-regulating the Bax protein line. Rasagiline can convert amyloid precursor (APP) into soluble APPalpha (sAPPalpha) with neuroprotective and neurotrophic effects through protein kinase C and mitogen-activated protein kinase-dependent activated alpha-secretase, thereby enhancing nerve growth factor glial cell-derived neuronal trophic factor (glial cell-derived neurotrophic, GDNF) and brain-derived neurotrophic factor (brain-derived neurotrophic factor), BDNF). Therefore, rasagiline has neuroprotective effect, neuroforming effect and long-term synergistic effect. Fig. 1 is the structural formula of rasagiline |
pharmacokinetics | the absorption of this product is rapid, reaching the peak plasma (ρmax) after 0.5h, and the absolute bioavailability is 36% after a single dose. food will not affect the peak time of this product, but ρmax and AUC may reduce 60% and 20% respectively. when combined with high-fat food, the influence of AUC is obvious, therefore, this product can be used with or without food. After a single intravenous dose is distributed, the average distribution volume of this product is 243L, and the plasma protein binding rate is about 60% ~ 70%. Metabolism of this product occurs almost completely in the liver before excretion. The metabolic pathways are mainly N-dealkylation and/or hydroxylation to produce 1-aminoindan, 3-hydroxy-N-propargyl -1-aminoindan and 3-hydroxy-1-aminoindan. In vitro tests show that the two metabolic pathways are dependent on CYP450 enzyme system, mainly CYP1A2. The chelation of rasagiline and its metabolite found that the main elimination pathway is the production of glucuronide. Aminoindan is the main active metabolite, but its MAO-B inhibition is very weak. The metabolites of this product are mainly excreted by urine (62.6%), followed by feces (21.8%). The total excretion measured after 38 days can reach 84.4% of the oral dose, and only less than 1% is excreted from urine by prototype. The pharmacokinetic linear relationship of this product is in the dose range of 0.5~2mg, and the phase attenuation period is 0.6~2h. |
slagilan | slagilan is an irreversible monoamine oxidase type B inhibitor that can delay disease progression (about 9 months) and postpone the use of levodopa. Although the effect of delaying disease progression began to weaken after 1 year of use, it can significantly improve motor symptoms. Studies have shown that in PD patients treated with levodopa, taking slegilam can significantly delay disease progression, reduce levodopa's efficacy regression, rarely switch and freeze, and can delay levodopa Use and have better long-term effects. |
levodopa | levodopa is the most effective oral drug for the treatment of PD. it plays the role of supplementing dopamine (DA) neurotransmitter, can reduce tremor, and has the most significant improvement on bradycardia and rigidity, but the long-term application of "on-off" effect, end effect and other adverse reactions are obvious. Clinical often combined medication, reduce the dosage of levodopa to alleviate adverse reactions. Such as combined with DA receptor agonists, monoamine oxidase (MAO) -B inhibitors and catecholamine-O-methyltransferase (COMT) inhibitors. However, with the extension of medication time, adverse reactions will still increase. |
drug interaction | rasagline cannot be combined with other MAO inhibitors or pethidine, and hypertensive crisis may occur after combined use. If it must be used, the medication time between the two should be at least 14 d. Can not be combined with fluoxetine or fluvoxamine, at least 5 weeks after fluoxetine withdrawal or at least 14 days after the withdrawal of fluoxetine or fluoxetine or fluvoxamine. Nor can it be combined with tricyclic/tetracyclic antidepressants, and serious adverse reactions have been reported. The results of in vitro metabolism studies show that since CYP4501A2 is the main metabolic enzyme of rasagilan, the AUC of the former can increase by 83% after combination with ciprofloxacin (CYP1A2 inhibitor), so it may change the plasma level of rasagilan when combined with CYP1A2 inhibitor, which should be paid attention. Rasagilan is not used in combination with dextromethorphan or sympathomimetic drugs such as ephedrine or pseudoephedrine in cold medicine. (2016-03-02) |
contraindications | mild liver function damage; those who want to become pregnant; lactating women should use it with caution and are allergic to any of the ingredients in this preparation; severe liver function Damage; simultaneous use of monoamine oxidase inhibitors or pethidine is prohibited. |
toxic substance data | information provided by: pubchem.ncbi.nlm.nih.gov (external link) |