Suvorexant

Absorption

Peak concentrations occur at a median Tmax of 2 hours under fasted conditions. Ingestion of suvorexant with a high-fat meal has no effect on AUC or Cmax, but may delay Tmax by approximately 1.5 hours. Mean absolute bioavailability of 10 mg is 82%.

Toxicity

Dose-related somnolence and CNS depression are the most common adverse effects associated with the use of suvorexant. It has also been shown to impair driving skills and may increase the risk of falling asleep while driving. Next-day impairments are found to be highest if suvorexant is taken with less than a full night of sleep remaining, with higher doses, or if co-administered with other CNS depressants or CYP3A inhibitors. Complex behaviours such as sleep driving, preparing and eating food, and making phone calls have been reported in association with the use of hypnotics such as suvorexant. A dose-dependant increase in suicidal ideation has been observed, especially in patients with a previous diagnosis of depression. Sleep paralysis, hypnagogic/hypnopompic hallucinations including vivid and disturbing perceptions, and mild cataplexy have also been reported. There are no adequate studies in pregnant women to ensure its safety during pregnancy or breast feeding.

Description

Suvorexant, a dual orexin receptor antagonist marketed under the trade name Belsomra®, discovered and developed by Merck for the treatment of insomnia, was approved by the US FDA in August 2014 and became available in Japan in November of the same year. The drug’s mechanism of action operates through the competitive blockade of wake-promoting neuropeptides orexin A and orexin B toward receptors orexin receptor type 1 and orexin receptor type 2, which are believed to modulate sleep-wake cycles.

The Uses of Suvorexant

Suvorexant (MK-4305) is a dual (non-selective) orexin receptor antagonist in development by Merck & Co. for the treatment of insomnia. It works by turning off wakefulness rather than by inducing sleep. Users of higher doses had an increased rate of suicidal ideation.

Indications

Suvorexant is indicated for the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance.

Background

Suvorexant is a selective dual antagonist of orexin receptors OX1R and OX2R that promotes sleep by reducing wakefulness and arousal. It has been approved for the treatment of insomnia.

Definition

ChEBI: Suvorexant is an aromatic amide obtained by formal condensation of the carboxy group of 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid with the secondary amino group of 5-chloro-2-[(5R)-5-methyl-1,4-diazepan-1-yl]-1,3-benzoxazole. An orexin receptor antagonist used for the management of insomnia. It has a role as a central nervous system depressant and an orexin receptor antagonist. It is a member of 1,3-benzoxazoles, a member of triazoles, a diazepine, an aromatic amide and an organochlorine compound.

Biological Activity

Suvorexant is a dual orexin receptor (OXR) antagonist that blocks both OX1R and OX2R (Kis = 1.2 and 0.60 nM, respectively). It reduces locomotor activity and promotes sleep by inhibiting the binding of orexin A and B. In rats, suvorexant decreases self-administration of, and conditioned place preference for, cocaine ( | 16186 | ISO60176). It also decreases dopamine levels in the rat ventral striatum following a cocaine-induced increase. Formulations containing suvorexant are used in the treatment of insomnia.  Suvorexant is regulated as a Schedule IV compound in the United States. This compound is also available as an analytical reference standard.

Synthesis

Commercially available acid 240 was first subjected to a copper-assisted substitution reaction involving 1,2,3-triazole in DMF at elevated temperatures. Although these conditions resulted in an excellent yield of a triazole-substituted product, an approximate 4:1 ratio of the desired 2-arylated triazole 241 and the undesired 1-arylated triazole byproduct were recovered from the reaction. The mixture was then treated with N,Ndimethylethylenediamine in acid to sequester copper. Next, the mixture of arylated triazoles was carefully subjected to sodium tbutoxide in DMF and ethyl acetate to form the corresponding sodium salts, and interestingly it was found that the desired sodium salt of 241 could be isolated based on its solubility profile under these conditions. Acidification of the desired carboxylate salt using dilute HCl gave rise to acid 241 in 60% yield across the fourstep sequence. Next, subjection of this acid to oxalyl chloride in chilled DMF generated the acid chloride 242 in excellent yield. This crude acid chloride was used immediately in the next step of the synthetic sequence.

For the preparation of the diazepine-containing portion of suvorexant, the synthesis commenced with the condensation of commercial 2-amino-4-chlorophenol (243) with thiophosgene (244) to furnish benzoxazole 245. Next, thiol 245 was converted to the corresponding chloride prior to exposure to Boc-protected ethylenediamine 246 under basic conditions. This was followed by a Michael addition of the resulting aminobenzoxazole and methyl vinyl ketone (MVK). The result of this sequence of reactions delivered aminobenzoxazole ketone 247 in 75% yield over the three steps. Next, subjection of the carbamate to methanesulfonic acid removed the Boc functionality and this was followed by an intramolecular reductive amination sequence to construct the diazaepine ring. Acid¨Cbase workup ultimately provided the racemic diazepine 248 in 92% yield from 247. Next, salt formation with a benzoyl tartaric acid and subsequent recrystallization upgrade using isopropyl acetate and methanol at ambient temperature was used to resolve racemic 248 into the tartrate salt 249 in 27% yield and excellent enantiomeric excess. Finally, salt 249 was freebased using sodium hydroxide prior to exposure to the crude acid chloride 242 under basic conditions to ultimately deliver suvorexant (XXX) in 95% yield and 99% ee across the twostep sequence.

Metabolism

Suvorexant is primarily metabolized by cytochrome-P450 3A4 enzyme (CYP3A4) with a minor contribution from CYP2C19. Major circulating metabolites are suvorexant and a hydroxy-suvorexant metabolite, which is not expected to be pharmacologically active. There is potential for drug-drug interactions with drugs that inhibit or induce CYP3A4 activity.

Metabolism

Suvorexant is primarily metabolized by cytochrome-P450 3A4 enzyme (CYP3A4) with a minor contribution from CYP2C19. Major circulating metabolites are suvorexant and a hydroxy-suvorexant metabolite, which is not expected to be pharmacologically active. There is potential for drug-drug interactions with drugs that inhibit or induce CYP3A4 activity.