Almotriptan

Description

Almotriptan was first marketed in Spain as a new medicine against acute attacks of migraine. It is the fifth agent belonging to the “triptan” class to be launched after sumatriptan, naratriptan, zolmitriptan and rizatriptan. This close structural analog of sumatriptan can be prepared in six steps from 4-nitrobenzylsulfonyl chloride with a Fischer indole synthesis as the key step. Almotriptan acts as a dual 5-HT_1D/1B agonist with a 35 to 51-fold selectivity versus 5-HT_1A and 5-HT₇ receptors respectively as well as having insignificant affinity for the most relevant nonserotonergic receptors (K1＞1μM). Its agonistic effect on 5-HT,n receptors of trigeminal sensory neurons turns off neurogenic inflammation by inhibiting the release of neuropeptides such as calcitonin gene-related peptide, neurokinin A and substance P. Concomitantly, its action on the 5-HT_1B receptors in meningeal arteries relieves the vasodilatation of these vessels associated with migraine attacks. Almotriptan causes selective concentration-dependent vasoconstriction of human meningeal and temporal arteries (with EC₅₀ of 0.03 and 0.7 μM) compared to basilar (EC₅₀ = 3.5 μM) and pulmonary arteries (EC₅₀＞10μM) or rabbit mesenteric and renal arteries (EC₅₀＞100 μM). Although it is predominantly cleared by the kidneys as unchanged drug (45%) or transformed into inactive metabolites by monoamine oxidase A (MAO-A) and CYP3A4 enzymes in the liver, almotriptan has the highest oral bioavailability (70%) of the triptans and has a half-life of 3.5 h. The therapeutic dose of 12.5 mg is well tolerated, shows a rapid onset of action (30 min) and low recurrence rate compared to sumatriptan.

Originator

Almirall Prodesfarma (Spain)

Uses

Serotonin 5HT1B /1D-receptor agonist

Definition

ChEBI: An indole compound having a 2-(dimethylamino)ethyl group at the 3-position and a (pyrrolidin-1-ylsulfonyl)methyl group at the 5-position.

Manufacturing Process

To a solution of previously dried 1-[[2-carboxy-3-(2-dimethylaminoethyl)-5- indolyl]methanesulphonyl]-pyrrolidine (1.6 g; 0.0442 moles) in anhydrous quinoline (75 ml) and under atmosphere of nitrogen, cuprous oxide (160 mg; 0.0011 moles) was added. The reaction mixture was heated to 190°C for 15 minutes, stirred to room temperature, poured into a mixture of 1 N hydrochloric acid (150 ml) and ethyl acetate (50 ml), shaken and decanted. The aqueous solution was washed several times with ethyl acetate, then solid sodium bicarbonate was added until pH = 7.8, and washed with n-hexane to eliminate the quinoline. The aqueous solution was made alkaline with solid potassium carbonate and extracted with ethyl acetate. The organic solution was dried (Na2SO4), the solvent removed under reduced pressure when a dark oil was obtained (1.3 g; yield 92%). This product was purified by column chromatography with silica gel and methylene chloride:ethanol:ammonium hydroxide (60:8:1) as eluent and a white foam (0.8 g) of 1-[[3-(2- dimethylaminoethyl)-5-indolyl]methanesulphonyl]-pyrrolidine was obtained. To a solution of the above product (0.8 g) in acetone (30 ml), a few drops of hydrogen chloride saturated dioxan solution, were added. The precipitated solid was collected by filtration, washed with acetone and dried to give 1-[(3- (2-(dimethylamino)ethyl)-5-indolyl)methanesulphonyl]-pyrrolidine hydrochloride (0.75 g). Melting point 218°-220°C.
In practice it is usually used as malate salt.

brand name

Almogran

Therapeutic Function

Migraine therapy

Clinical Use

5HT1 receptor agonist:
Acute relief of migraine

Drug interactions

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

Metabolism

The major biotransformation route is via monoamine oxidase (MAO-A) mediated oxidative deamination to the indole acetic metabolite. Cytochrome P450 (3A4 and 2D6 isozymes) and flavin mono-oxygenase are other enzymes involved in the metabolism of almotriptan. None of the metabolites are significantly active pharmacologically. More than 75% of a dose is eliminated in urine, and the remainder in faeces. Approximately, 50% of the urinary and faecal excretion is unchanged almotriptan.