Alniditan

Alniditan is a selective serotonin 5-HT_1B and 5-HT_1D receptor agonist with migraine-preventive effects which was never marketed. It was under development for treatment of migraine via subcutaneous injection in the 1990s and reached phase 3 clinical trials for this indication prior to the discontinuation of its development.

Pharmacology

Pharmacodynamics

Alniditan acts as a selective serotonin 5-HT_1B and 5-HT_1D receptor full agonist. To a much lesser extent, it is also a full agonist of the serotonin 5-HT_1A receptor and an agonist of the serotonin 5-HT_2B receptor. Conversely, alniditan is essentially inactive at the serotonin 5-HT_1E, 5-HT_1F, and 5-HT_2A receptors. The broad receptor interactions of alniditan have been studied and reported.

Pharmacokinetics

The elimination half-life of alniditan is relatively long at 8 to 13hours.

Chemistry

Synthesis

The sizeable number of serotonergic drugs for treating migraines all incorporate the indole nucleus found in serotonin itself. It is thus of interest that a compound based on a benzopyran manifests much the same activity.
Alkylation of phenol with 2-bromobutyrolactone leads to the ether. Oxidation of that product with chromium trioxide then leads to the substituted succinic anhydride. Treatment of anhydride with polyphosphoric acid leads to the acylation of the aromatic ring and the formation of the benzopyranone ring. The ketone is then selectively reduced by any of several methods, as, for example, conversion to a dithiolane followed by Mozingo reduction to 6. The carboxylic acid is next reduced to the corresponding aldehyde by successive conversion to an acid chloride followed by hydrogenation in the presence of thiophene. A second hydrogenation in the presence of benzylamine leads to the reductive amination product. Michael addition of the amino group in 8 to acrylonitrile leads to a 1,4-addition and the formation of. Reduction of the nitrile affords the diamine. Reaction of this last diamine with tetrahydropyrimidine chloride, itself formed by treatment of trimethylene urea with phosphorus oxychloride, leads to the displacement of halogen by the terminal, and thus more accessible, amino group in. There is thus formed the serotonergic agent alniditan.