Залеплон

Описание

Zaleplon was introduced in Sweden and Denmark as a new treatment for insomnia, particularly in patients who have difficulty in falling asleep. Zaleplon is a non-benzodiazepine compound and is the first in a new generation belonging to the pyrazolopyrimidine class, showing therefore fewer benzodiazepine-like side effects. It can be synthesized in 3 steps from the corresponding acetophenone, the key step being the cyclization of the appropriate enaminone with 3-aminopyrazole-4-carbonitrile. Biochemically, Zaleplon is a full agonist at the benzodiazepine o)1 site of the gaba-A receptor complex, but its behavioural profile remains distinct from both benzodiazepine (e.g. Lorazepam) or non-benzodiazepine (e.g. Zopiclone or Zolpidem) sedativehypnotic drugs. Clinical pharmacokinetic analysis showed rapid absorption and elimination. In man, the main metabolic route was oxidative giving the major metabolites 5-oxo Zaleplon and its N-desethyl analog. Both were shown to have no effect at central benzodiazepine receptors and to be rapidly excreted as glucuronides. In patients with chronic insomnia, Zaleplon at 5 and 10 mg/kg significantly reduced sleep latency and improved the quality of sleep compared with placebo without altering the normal sleep architecture. Given its short halflife, the next-day residual effects such as hangover are minimized. It may have some advantages over benzodiazepines regarding unwanted amnesic effects and psychomotor impairment. There was no evidence for the occurrence of rebound insomnia at 10 mg/kg.

Химические свойства

Off-White Powder

Использование

Selective non-benzodiazepine GABAA receptor agonist

Определение

ChEBI: A pyrazolo[1,5-a]pyrimidine having a nitrile group at position 3 and a 3-(N-ethylacetamido)phenyl substituent at the 7-position.

Общее описание

Zaleplon (Sonata, a pyrazolopyrimidine) isanother short-acting nonbenzodiazepine hypnotic.Pharmacologically and pharmacokinetically, zaleplon is similarto zolpidem; both are hypnotic agents with short halflives.It also has selective high affinity for α1-subunit containingBzRs but produces effects at other BzR/GABAAsubtypes as well. Zaleplon is well absorbed following oraladministration with an absolute bioavailability of approximately30% because of significant presystemic metabolism.It exhibits a mean half-life of approximately 1 hour, with lessthan 1% of the dose excreted unchanged in urine. It is primarilymetabolized by aldehyde oxidase to 5-oxo-zaleplon andis also metabolized to a lesser extent by CYP3A4. Ndemethylationyields desethylzaleplon, which is quickly converted,presumably by aldehyde oxidase, to 5-oxo-desethylzaleplon.These oxidative metabolites are thenconverted to glucuronides and eliminated in urine. All of zaleplon’smetabolites are pharmacologically inactive. It mayhave a more rapid onset (about 1 hour) and termination of actionthan zolpidem, and therefore, it is good to initiate sleepinstead of keeping sleep.

Биологическая активность

Non-benzodiazepine agent that acts as an agonist at the benzodiazepine site. Displays hypnotic, anxiolytic, myorelaxant and anticonvulsant activity.

Фармакокине?тика

Zaleplon displays a unique binding profile with GABAA that is distinct from the benzodiazepines but similar to that of zolpidem. Because of it greater potency for GABAA, the starting dose for zaleplon is comparable to that of zolpidem. It is rapidly absorbed, with a log P of 1.23, although only 30% of the dose is bioavailable because of rapid first-pass metabolism via liver cytosolic aldehyde oxidase/xanthine oxidase (molybdenum hydroxylases) to its major ring oxidation product, 5-oxo-zaleplon metabolite. The minor metabolism pathways include N-dealkylation from microsomal oxidation via CYP3A4 to N-desethyl-zaleplon and N-desethyl-5-oxo-zaleplon. It is rapidly metabolized by the liver, with an elimination half-life of approximately 1 hour. The oxidative metabolites are inactive, conjugated with glucuronic acid, and eliminated in the urine. Inhibitors of CYP3A4 and aldehyde oxidase can increase the plasma concentration of zaleplon significantly, although this usually does not require dosage modification. Zaleplon does not accumulate with once-daily administration and displays linear pharmacokinetics in the therapeutic range.

Метаболизм

The elimination half-life of zaleplon is increased in patients with hepatic insufficiency, requiring an adjustment in dosage. High-fat meals increase the time to peak concentration and decrease the plasma concentration without affecting the half-life. These results suggest that for faster sleep onset, zaleplon should not be administered either with or immediately after a meal, which increases the time to reach peak plasma concentrations. In short-term studies (2–5 weeks), zaleplon has been shown to improve sleep quality with minimal adverse effects and no significant rebound insomnia on stopping the drug. Because of its short elimination half-life, zaleplon is quite good at getting people to sleep but is not as good at keeping people asleep. Unlike with zolpidem and eszopiclone, it has been proposed that if the patient awakens in the middle of the night (with ≥4 hours of sleep time remaining), another dose of zaleplon can be taken.