Eletriptan

Description

Eletriptan, the seventh member of the triptan class of antimigraine drugs was launched in Switzerland for the acute treatment of migraine. The 5-step synthesis of this conformationally restricted analog of sumatriptan involves the deprotonation of 5- bromoindole with Grignard reagent at the position C3 followed by a condensation with NCbz- D-proline acid chloride to afford the key Cbz-D-prolyl intermediate. After reduction with LiAIH4, the sulfone moiety was introduced in postion 5 by a palladium cross-coupling Heck reaction using the phenylvinyl sulfone. Eletriptan is a 5-HT receptor agonist that binds to 5-HT_1B, 5HT_1D and 5HT_1F receptors with high potency. Activation of these receptors causes constriction of extracerebral intracranial vessels, abolition of the dural extravasation and neurogenic inflammation, and inhibition of trigeminal neuronal discharge. Eletriptan was found to be the most potent agonist at the 5-HT_1D receptor compared to the other triptans with pEC₅₀ value of 9.2. In thousands of participants in clinical trials, eletriptan has acted more effectively and more rapidly than sumatriptan to relieve pain from mild to severe attacks of migraine. Eletriptan also reduced time lost for ordinary activity to patients with migraine attacks when compared to placebo and when compared to sumatriptan. Eletriptan was also superior to sumatriptan in terms of relieving functional disability, nausea, photophobia and phonophobia. Unlike other compounds of its class, eletriptan has a positive logD value, that could underlie its rapid and complete oral absorption and may be suggestive of a good brain penetration. The oral biovailability of Eletriptan is approximately 50% (14% for Sumatriptan) with a half life of 5.7h (2h for Sumatriptan). Eletriptan was well tolerated with mild to moderate adverse events including asthenia, somnolence, dizziness and nausea. Eletriptan is a new potent and fast-acting triptan for the treatment of migraine attacks.

Chemical Properties

Yellow Foam

Originator

Pfizer (US)

Uses

A serotonin 5-HTIB/ID receptor agonist. Antimigrene

Uses

Eletriptan is a selective serotonin 5-HT1B and 5-HT1D receptor agonist and used to treat migraines (1,2,3).

Definition

ChEBI: Eletriptan is an N-alkylpyrrolidine, being N-methylpyrrolidine in which the pro-R hydrogen at position 2 is substituted by a {5-[2-(phenylsulfonyl)ethyl]-1H-indol-3-yl}m thyl group.

Manufacturing Process

A mixture of the appropriate phenyl vinyl sulfone, tri-o-tolylphosphine, palladium (II) acetate, triethlamine and (R)-5-bromo-3-(Nmethylpyrrolidinylmethyl)-1H-indole in anhydrous acetonitrle was heated at reflux under nitrogen. The resultant reaction mixture was evaporated under reduced pressure, and the residue was column chromatographed using silica gel and elution with methylene chloride/absolute ethanol/ammonia to afford the (R )-5-trans-(2-phenylsulfonylethenyl)-3-(N-methylpyrrolidin-2-ylmethyl)- 1H-indole.
A solution of (R)-5-trans-(2-phenylsulfonylethenyl)-3-(N-methylpyrrolidin-2- ylmethyl)-1H-indole and 10% Pd/C in ethanolic hydrogen chloride (prepared from absolute ethanol and acetyl chloride and N,N-dimethylformamide was shaken under a hydrogen atmosphere at room temperature). The resultant reaction mixture was filtered through diatomaceous earth (Celite trademark), washed with absolute ethanol, and the combined filtrates were evaporated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic phase was separated, washed with water, brine, dried(Na2SO4), and evaporated under reduced pressure to afford a oil product. Column chromatography of this product using silica gel and elution with methylene chloride/absolute ethanol/ammonia afforded the appropriate (R)-5- (2-phenylsulfonylethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole.
The salt eletriptan hydrobromide may be produced by reaction of the (R)-5- (2-phenylsulfonylethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole with hydrobromic acid.

brand name

Relpax

Therapeutic Function

Serotonin agonist

General Description

Eletriptan, introduced into the market in 2002, is the newesttriptan with highest affinity for 5-HT1B, 5-HT_1D, and 5-HT_1Freceptors. It is one of the most lipophilic triptans marketedto date and is well tolerated and safe across its dosing rangeof 20 to 80 mg. However, it is metabolized primarily(>90%) by CYP3A4 isozyme to its active metabolite, theN-desmethyleletriptan, which accounts for approximately10% to 20% of the plasma concentration of that observedfor parent drug. Thus, coadministration of eletriptan withpotent CYP3A4 inhibitors such as ketoconazole, itraconazole,nefazodone, troleandomycin, clarithromycin, ritonavir,and nelfinavir may require dose reduction and closer monitoringfor CNS side effects. Furthermore, becauseeletriptan and its active metabolite, N-desmethyleletriptan,are also substrates for the P-glycoprotein efflux pumps thatare responsible for their removal from the brain, coadministrationof eletriptan with a known P-glycoprotein inhibitorand/or inducer such as digoxin, diltiazem, verapamil, or St.John’s Worth would result in higher brain levels of its activemetabolite, and thus a higher rate of the CNS side effectsreported for this drug.

Clinical Use

5HT1 receptor agonist:
Acute relief of migraine

Drug interactions

Potentially hazardous interactions with other drugs
Antibacterials: concentration increased by clarithromycin and erythromycin - avoid.
Antidepressants: increased risk of CNS toxicity with citalopram - avoid; possibly increased serotonergic effects with duloxetine and venlafaxine; increased serotonergic effects with St John’s wort - avoid
Antifungals: concentration increased by itraconazole and ketoconazole - avoid.
Antivirals: concentration increased by indinavir and ritonavir - avoid.
Dapoxetine: possible increased risk of serotonergic effects - avoid for 2 weeks after stopping 5HT1 agonists
Ergot alkaloids: increased risk of vasospasm - avoid.

Metabolism

In vitro studies indicate that eletriptan is primarily metabolised by hepatic cytochrome P-450 enzyme CYP3A4. This finding is substantiated by increased plasma concentrations of eletriptan following
known selective and potent CYP3A4 inhibitors. In vitro studies also indicate a small involvement of CYP2D6 although clinical studies do not indicate any evidence of polymorphism with this enzyme.
There are two major circulating metabolites identified that significantly contribute to plasma radioactivity following administration of 14C-labelled eletriptan. The metabolite formed by N-oxidation, has demonstrated no activity in animal in vitro models. The metabolite formed by N-demethylation, has been demonstrated to have similar activity to eletriptan in animal in vitro models. A third area of radioactivity in plasma has not been formally identified, but is most likely to be a mixture of hydroxylated metabolites which have also been observed excreted in urine and faeces.
The plasma concentrations of the N-demethylated active metabolite are only 10-20% of those of parent, so would not be expected to significantly contribute to the therapeutic action of eletriptan. Non-renal clearance accounts for approximately 90% of the total clearance indicating that eletriptan is eliminated primarily by metabolism.