MT2 receptor ( pKi = 9.8 ); MT1 receptor ( pKi = 9.45 )

体外活性：他司美琼（又名BMS-214778；VEC-162；商品名：Hetlioz）是一种新型昼夜节律调节剂，是第一个治疗非24小时睡眠觉醒障碍（Non-24）的产品经 FDA 或欧洲药品管理局 (EMA) 批准。 Tasimelteon 是一种有效且特异性的褪黑激素（MT1 和 MT2）受体激动剂，对 MT2 受体的亲和力高出 2 - 4 倍。长期服用他司美琼是安全且耐受性良好的。 Non-24 和失眠患者的安慰剂对照数据支持了这一点。激酶测定：他司美琼是一种选择性双重褪黑激素受体 (MT1/MT2) 激动剂，对 MT2 受体的亲和力高出 2.1-4.4 倍，据信可介导昼夜节律相移（NIH-3T3 中 Ki = 0.0692 nM 和 Ki = 0.17 nM） CHOeK1 细胞），比 MT1 受体（Ki = 0.304 nM 和 Ki = 0.35 nM，分别）。

在大鼠和猴子中，他司美琼的半衰期约为 2 小时，比褪黑激素的半衰期长。他司美琼的平均绝对生物利用度约为 38.3%。他司美琼代谢物的口服与静脉注射暴露比率较高以及静脉注射后代谢物与母体比率降低表明，尽管他司美琼经历首过代谢，但其代谢的很大一部分发生在系统后而不是系统前。口服和静脉注射他司美琼均具有良好的耐受性

Absorption, Distribution and Excretion
Following oral administration of radiolabeled tasimelteon, 80% of total radioactivity was excreted in urine and approximately 4% in feces, resulting in a mean recovery of 84%. Less than 1% of the dose was excreted in urine as the parent compound.
The apparent oral volume of distribution of tasimelteon at steady state in young healthy subjects is approximately 56 - 126 L.

---

Metabolism / Metabolites
Tasimelteon is extensively metabolized. Metabolism of tasimelteon consists primarily of oxidation at multiple sites and oxidative dealkylation resulting in opening of the dihydrofuran ring followed by further oxidation to give a carboxylic acid. CYP1A2 and CYP3A4 are the major isozymes involved in the metabolism of tasimelteon. Phenolic glucuronidation is the major phase II metabolic route.

---

Biological Half-Life
The observed mean elimination half-life for tasimelteon is 1.3 ± 0.4 hours.

Hepatotoxicity
In several clinical trials, tasimelteon was found to be well tolerated. Serum enzyme elevations occurred in up to 10% of tasimelteon treated patients compared to 5% of placebo controls, but instances of clinically apparent liver injury were not reported. In a combined analysis of 6 trials of tasimelteon given for an average of 1 year, ALT elevations above 3 times the ULN arose in 6.5% of tasimelteon treated subjects, but no elevations were above 10 times ULN, and none were associated with symptoms or jaundice. Most elevations were single values and resolved spontaneously without dose reduction or discontinuation. Tasimelteon has been available for a limited period of time, but has not been linked to instances of clinically apparent liver injury. Tasimelteon is metabolized by the cytochrome P450 system (predominantly CYP 1A2 and CYP3A4), which can result in significant drug-drug interactions, strong inhibitors of the enzymes increasing serum concentrations of tasimelteon and strong inducers decreasing them.
Likelihood score: E (unlikely cause of clinically apparent liver injury).
Drug Class: Sedatives and Hypnotics
Other Drugs in the Subclass, Melatonin and its Analogues: Melatonin, Ramelteon

---

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the use of tasmelteon during breastfeeding. Monitor the infant for drowsiness and adequate feeding, especially while nursing a newborn or preterm infant. Until more data become available an alternate drug may be preferred.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

---

Protein Binding
At therapeutic concentrations, tasimelteon is about 90% bound to proteins.

[1]. Expert Opin Investig Drugs . 2011 Jul;20(7):987-93.

[2]. Am J Ther . 2015 Sep-Oct;22(5):355-60.

[3]. J Clin Pharmacol. 2015 May; 55(5): 525–533.

Tasimelteon is a member of the class of 1-benzofurans that is propionamide in which one of the amide hydrogens is replaced by a [(1R,2R)-2-(2,3-dihydro-1-benzofuran-4-yl)cyclopropyl]methyl group. A melatonin receptor agonist used for the treatment of non-24-hour sleep-wake disorder. It has a role as a melatonin receptor agonist. It is a monocarboxylic acid amide, a member of 1-benzofurans and a member of cyclopropanes. It is functionally related to a propionamide.
Tasimelteon is a selective dual melatonin receptor agonist indicated for the treatment of Non-24-Hour Sleep-Wake Disorder (N24HSWD). Occurring commonly in blind individuals without light perception, this condition is often characterized by periods of night-time insomnia and day-time sleepiness. In blind individuals, a lack of light stimulation causes an extension of the 24-hour circadian cycle and can lead to progressively delayed sleep onset. By activating melatonin receptors MT1 and MT2 in the suprachiasmatic nucleus of the brain, tasimelteon has been shown to improve sleep by resynchronizing the circadian rhythm through its "non-photic" mechanism. Tasimelteon is currently the only drug available for the treatment of N24HSWD and was granted orphan drug status by the FDA in 2010.
Tasimelteon is a Melatonin Receptor Agonist. The mechanism of action of tasimelteon is as a Melatonin Receptor Agonist.
Tasimelteon is a melatonin receptor agonist that is used for the treatment of non-24 hour sleep-wake disorder in blind individuals. Tasimelteon therapy is associated with a low rate of serum enzyme elevations, but has not been implicated in cases of clinically apparent liver injury.

---

Drug Indication
Tasimelteon oral capsules are indicated for the treatment of non-24 hour sleep-wake disorder in adult patients and for the treatment of nighttime sleep disturbances in Smith-Magenis Syndrome in patients ≥16 years old. Tasimelteon oral suspension is indicated for the treatment of nighttime sleep disturbances in Smith-Magenis syndrome in patients 3 to 15 years of age.
FDA Label
Hetlioz is indicated for the treatment of Non-24-Hour Sleep-Wake Disorder (Non-24) in totally blind adults. ,
Treatment of non-24-hour sleep-wake disorder in the totally blind

---

Mechanism of Action
Tasimelteon is a selective dual agonist of the melatonin receptors MT1 and MT2.

C15H19NO2

245.32

245.141

C, 73.44; H, 7.81; N, 5.71; O, 13.04

609799-22-6

Tasimelteon-d5; 1962124-51-1

10220503

Solid powder

1.1±0.1 g/cm3

442.6±24.0 °C at 760 mmHg

78°C(lit.)

221.4±22.9 °C

0.0±1.1 mmHg at 25°C

1.564

1.75

38.33

1

2

4

18

318

2

O1C([H])([H])C([H])([H])C2C1=C([H])C([H])=C([H])C=2[C@]1([H])C([H])([H])[C@@]1([H])C([H])([H])N([H])C(C([H])([H])C([H])([H])[H])=O

PTOIAAWZLUQTIO-GXFFZTMASA-N

InChI=1S/C15H19NO2/c1-2-15(17)16-9-10-8-13(10)11-4-3-5-14-12(11)6-7-18-14/h3-5,10,13H,2,6-9H2,1H3,(H,16,17)/t10-,13+/m0/s1

N-[[(1R,2R)-2-(2,3-dihydro-1-benzofuran-4-yl)cyclopropyl]methyl]propanamide

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

配方 1 中的溶解度: ≥ 2.5 mg/mL (10.19 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

---

配方 2 中的溶解度: ≥ 2.5 mg/mL (10.19 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

---

View More

配方 3 中的溶解度: ≥ 2.5 mg/mL (10.19 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清 DMSO 储备液添加到 900 μL 玉米油中并混合均匀。

---

配方 4 中的溶解度: 5%DMSO + Corn oil: 2.0mg/ml (8.15mM)

---

请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。