Tasimelteon

Structural formula
General
Non-proprietary name	Tasimelteon
other names	(1 R , 2 R ) - N - [2- (2,3-Dihydrobenzofuran-4-yl) cyclopropylmethyl] propionic acid amide (1 R , 2 R ) - N - [2- (2,3-Dihydrobenzofuran-4-yl) cyclopropylmethyl] propanamide
Molecular formula	C 15 H 19 NO 2
Brief description	white crystalline powder
External identifiers / databases
CAS number 609799-22-6 EC number 612-059-5 ECHA InfoCard 100.114.889 PubChem 10220503 DrugBank DB09071 Wikidata Q7687250
Drug information
ATC code	N05 CH03
Drug class	Hypnotics
Mechanism of action	Melatonin receptor agonist
properties
Molar mass	245.31 g · mol -1
Physical state	firmly
Melting point	78 ° C 74 ° C ( anhydrate )
solubility	Well soluble in cyclohexane, methanol, 95% ethanol, water, 0.1 N HCl
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed GHS hazard labeling no classification available
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Tasimelteon is a drug from the group of sleeping pills (hypnotics), which is used in the treatment of sleep-wake disorders when deviating from the 24-hour rhythm .

Chemical and physical properties

Tasimelteon has two stereocenters. In addition to the medicinally used trans-1 R , 2 R isomer (top left in the figure), there are three other stereoisomers that do not arise in the synthesis.

Tasimelteon is a white to cream-colored crystalline non-hygroscopic substance, soluble in water at physiologically relevant pH values ​​and readily soluble in alcohols, cyclohexane and acetonitrile.

The compound occurs in two crystal forms. It is an anhydrate that melts at 74 ° C and a hemihydrate . The hemihydrate releases the water of hydration from around 35 ° C and converts into the anhydrate form. The anhydrate crystallizes in a monoclinic lattice with the space group P 2 ₁ , the hemihydrate in a tetragonal lattice with the space group P 4 ₃ 2 ₁ 2.

Clinical information

Tasimelteon in the US in January 2014 Hetlioz ( Vanda Pharmaceuticals approved) for the treatment of sleep-wake disorder with deviation from the 24-hour cycle ( non-24-hour sleep-wake disorder , non-24 ).

In Europe, Hetlioz was approved as an orphan drug for the treatment of sleep-wake disorders with deviations from the 24-hour rhythm of blind people without any light perception in July 2015. The effectiveness has been demonstrated in two randomized, double-blind, placebo-controlled, multicenter parallel group studies (SET and RESET) in completely blind patients with non-24.

The drug is used orally and requires a prescription.

Pharmacological properties

Mechanism of action (pharmacodynamics)

Mechanism of action of tasimelteon (SCN = nucleus suprachiasmaticus )

Tasimelteon acts pharmacodynamically as an agonist on melatonin receptors 1 and 2 (binding affinity MT ₁ K _i : 0.35 nM, MT ₂ K _i : 0.17 nM). As G _i protein-coupled receptors , melatonin receptors modulate the neuronal activity of anatomically specific or wakefulness-determining neuronal networks such as the suprachiasmatic nucleus and the ascending reticular system in the reticular formation . It imitates the physiological effect of endogenous melatonin, which is necessary to regulate the circadian rhythm and which is only secreted by the epiphysis or reaches its maximum concentration in the dark.

The melatonin receptors are primarily located in the pituitary gland and in the suprachiasmatic nucleus (MT ₁ ), a core area in the hypothalamus and retina (MT ₂ ).

The mechanism of action of Tasimelteon can be understood from the scheme of the physiological effect of melatonin (see fig.).

Under the influence of light, transmission from the retina activates the suprachiasmatic nucleus, which in turn inhibits melatonin secretion in the pineal gland . The activity of the suprachiasmatic nucleus is increased by the decreasing melatonin concentration. As a result, the maintenance of sleep is terminated by the suprachiasmatic nerve by actively inhibiting the interneurons , which inhibit the specific or unspecific thalamic nuclei , which corresponds to the normal waking phase in the morning.

Since the specific and unspecific thalamic nuclei can have a stimulating effect on the entire cerebral cortex , it becomes so intuitively understandable that this forces cortical stimulus processing and makes it impossible to continue sleeping. Under the influence of darkness there is a decrease in activity of the suprachiasmatic nerve, which corresponds to an activation (inhibition of inhibition or disinhibition) of the pineal gland and thus triggers the melatonin concentration or secretion, which in turn actively via melatonin receptors (MT ₁ ) the N inhibit suprachiasmaticus. This activates the inhibiting thalamic interneurons, which inhibit the neurons of the specific and unspecific thalamic nuclei projecting into the cortex, which corresponds to the physiological sleep phase. Here, the cortical information processing is actively reduced, which subjectively corresponds to the feeling of fatigue. The drug tasimelteon mimics the hormone melatonin, which, as explained above, leads to an advance of the normal circadian rhythm if taken prematurely or, in the case of biosynthesis disorders (enzyme deficiency; mutations), blindness or severe retinal damage, the "melatonin-induced deep sleep phase" increases as well Shortened sleep phase and extended sleep phase.

Absorption and distribution in the body (pharmacokinetics)

Tasimelteon has an oral bioavailability of approx. 80%. The half-life is given as 1.3 ± 0.4 hours. After absorption, about 90% of Tasimelteon is bound to plasma proteins. It is metabolized primarily in the liver by CYP 1A2 , CYP 3A4 and CYP 2C19.

About 80% of the biotransformed active ingredient is eliminated via the kidneys and about 4% via the faeces.

toxicology

For mutagenicity both were Ames test and a micronucleus performed test that display both no mutagenic potential of the drug Tasimelteon.

No carcinogenicity could be determined in animal experiments (rats) , but a reduction in fertility .

Finished medicinal products

Hetlioz capsules 20 mg (EU, USA).

Individual evidence

1. ↑ ^{a b} rxlist.com
2. ↑ ^{a b c d e f g} Vanda Pharmaceuticals: Tasimelteon - Advisory Committee Meeting Briefing Materials , November 14, 2013, published on the FDA website, accessed July 19, 2014.
3. ↑ newdrugapprovals.org
4. ↑ ^{a b c d} Kaihang Liu, Xinbo Zhou, Zhejing Xu, Hongzhen Bai, Jianrong Zhu, Jianming Gu, Guping Tang, Xingang Liu, Xiurong Hu: Anhydrates and hemihydrate of tasimelteon: Synthesis, structure, and pharmacokinetic study in J. Pharm. Biomed. Anal. 151 (2018) 235-243, doi : 10.1016 / j.jpba.2017.12.035 .
5. ↑ This substance has either not yet been classified with regard to its hazardousness or a reliable and citable source has not yet been found.
6. ↑ ^{a b} Hetlioz ™ (tasimelteon) capsules 20 mg, Prescribing Information ", Vanda Pharmaceuticals Inc. December 12, 2014 ( fda.gov [PDF]).
7. ↑ EU / 3/10/841
8. ↑ Hetlioz - Summary of Product Characteristics . Retrieved April 20, 2019.
9. ^ Alfred Benninghoff: Anatomy 2, macroscopic anatomy, histology, embryology, cell biology. Cardiovascular system, lymphatic system, endocrine system, nervous system, sensory organs, skin. Urban & Fischer / Elsevier, Munich, ISBN 3-437-42350-9 .
10. ^ S. Rivara, M. Mor, A. Bedini, G. Spadoni, G. Tarzia: Melatonin Receptor Agonists: SAR and Application to the Treatment of Sleep-Wake Disorders. In: Current Topics in Medicinal Chemistry . 8 (11), 2008, pp. 954-968. doi: 10.2174 / 156802608784936719
11. ^ SA Ferguson, SMW Rajaratnam, D. Dawson: Melatonin agonists and insomnia. In: Expert Reviews. 10 (2) 2010, pp. 305-318, doi: 10.1586 / ern.10.1 .
12. ^ Takeda Pharmaceuticals North America, Inc. Tpna.com. Retrieved February 10, 2012.
13. ↑ Prolonged-Release Melatonin | Circadin® ". Circadin.com. February 1, 2012, Retrieved February 10, 2012.
14. ^ Servier ". Valdoxan.com. Retrieved February 10, 2012.
15. ↑ Darius. P. Zlotos, Ralf Jockers, Erika Cecon, Silvia Rivara, Paula A. Witt-Enderby: MT1 and MT2 Melatonin Receptors: Ligands, Models, Oligomers, and Therapeutic Potential. In: Journal of Medicinal Chemistry . 57 (8), 2014, pp. 3161-3185. doi: 10.1021 / jm401343c
16. ↑ hetlioz.com

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