Country of origin Originator First introduction Introduced by: Trade name CAS registry no
(mesylate salt) 171.24 267.33 (mesylate salt)
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. SAR dictates that a distance of no more than two carbon units between the aromatic ring and the amine is essential for conferring MAO-B specificity (IC50 = 14 nM vs. 700 nM for MAO-A). The inhibition of MAO-B prevents the degradation of dopamine, thereby, prolonging the action of dopamine to reduce the effects of dopaminergic neuronal deficit. Rasagiline has been approved for both initial monotherapy in patients with early disease as well as an adjunct treatment in patients with advanced disease. While levodopa, a dopamine precursor, is a standard line of treatment for PD, many patients begin to experience motor complications after several years of artificial dopaminergic stimulation. 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-amino-indan 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. As an irreversible inhibitor, frequent dosing is not necessary since the duration of action is not driven by half-life; regeneration of MAO-B is the critical factor in the duration of action. Rasagiline is rapidly absorbed with a Tmax of approximately 0.5 h and a Cmax of approximately 10 ng/mL with an absolute oral bioavailability of 36%. Its major metabolite, 1(R)-amino-indane, is generated via CYP1A2-mediated deamination in the liver and accounts for 20% of the 63% of elimination via the urine with an elimination half-life of 0.6-2 h. While this metabolite does not possess MAO-B inhibitory activity, it has been implicated in the neuroprotective, anti-apoptotic propensity of rasagiline. Several clinical trials involving more than 1000 patients with PD assessed the efficacy of rasagiline as a monotherapy or as an adjunct therapy. In one study, drug-naive patients were randomized to receive either placebo or ra-sagiline (1 or 2 mg/day) for 26 weeks. Both rasagiline-treated groups demonstrated statistically significant improvements in the mean change from baseline in the total score of the Unified Parkinson's Disease Rating Scale (UPDRS), the primary efficacy endpoint, compared to placebo. Another study involved the randomization of more advanced PD patients to receive placebo, rasagiline (1 mg/day), or entacapone (200 mg) concomitant with scheduled levodopa. For this study, the primary efficacy endpoint was the change from baseline in the mean number of hours spent in the "off" state, during the day. 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. Furthermore, the magnitude of these effects was comparable to that of entacapone. Overall, reported adverse events were comparable to placebo and included headache and arthalgia. Dyskinesia and accidental injury were also indicated as side effects when rasagiline was used as an adjunct to levodopa. As a substrate for CYP1A2, caution should be exercised when co-administering rasagiline with potent CYP1A2 inhibitors or inducers. The package insert advises against the concomitant use of rasagiline and antidepressants containing fluoxetine or fluvoxamine, suggesting a washout period of at least 5 weeks following the cessation of these CYP1A2 inhibitors. Also, rasagiline should not be used with other MAO inhibitors taken for the treatment of depression. Medical advice is required with over-the-counter drugs containing the cough suppressant dextromethorphan and nasal decongestants ephedrine and pseudo-ephedrine. Finally, the use of rasagiline is not recommended in patients under the age of 18.
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