ラサギリン 化學(xué)特性,用途語,生産方法
効能
パーキンソン病治療薬, 神経保護(hù)薬, モノアミン酸化酵素B(MAO-B)阻害薬
説明
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.
特性
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.
使用
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.
主な応用
Rasagiline is used alone or with other medications (such as levodopa/carbidopa) to treat symptoms of Parkinson's disease. It can help improve symptoms such as shakiness, stiffness, and difficulty moving. It can also help reduce the amount of "off" time (periods of slow movement or stiffness). Rasagiline belongs to a class of drugs known as MAO inhibitors. It works by increasing the levels of certain natural substances in the brain (such as dopamine, norepinephrine, serotonin). Parkinson's disease is thought to be caused by too little dopamine in the brain.
定義
ChEBI: An indane that consists of 1-aminoindane bearing an N-propargyl substituent. A selective, irreversible monoamine oxidase-B inhibitor.
適応癥
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.
薬物動(dòng)態(tài)學(xué)
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.
臨床応用
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.
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原材料
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