Danavorexton
(Synonyms: TAK-925) 目录号 : GC65550
Danavorexton 是促食素受体 (orexin receptor) 的激动剂。
Cas No.:2114324-48-8
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Danavorexton is an orexin receptor agonist[1].
[1]. International Nonproprietary Names for Pharmaceutical Substances (INN). WHO Drug Information, Vol. 34, No. 2, 2020.
| Cas No. | 2114324-48-8 | SDF | Download SDF |
| 别名 | TAK-925 | ||
| 分子式 | C21H32N2O5S | 分子量 | 424.55 |
| 溶解度 | DMSO : ≥ 50 mg/mL (117.77 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.3554 mL | 11.7772 mL | 23.5544 mL |
| 5 mM | 0.4711 mL | 2.3554 mL | 4.7109 mL |
| 10 mM | 0.2355 mL | 1.1777 mL | 2.3554 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Orexin 2 receptor-selective agonist Danavorexton improves narcolepsy phenotype in a mouse model and in human patients
Proc Natl Acad Sci U S A 2022 Aug 30;119(35):e2207531119.PMID:35994639DOI:10.1073/pnas.2207531119.
Narcolepsy type 1 (NT1) is a sleep disorder caused by a loss of orexinergic neurons. Narcolepsy type 2 (NT2) is heterogeneous; affected individuals typically have normal orexin levels. Following evaluation in mice, the effects of the orexin 2 receptor (OX2R)-selective agonist Danavorexton were evaluated in single- and multiple-rising-dose studies in healthy adults, and in individuals with NT1 and NT2. In orexin/ataxin-3 narcolepsy mice, Danavorexton reduced sleep/wakefulness fragmentation and cataplexy-like episodes during the active phase. In humans, Danavorexton administered intravenously was well tolerated and was associated with marked improvements in sleep latency in both NT1 and NT2. In individuals with NT1, Danavorexton dose-dependently increased sleep latency in the Maintenance of Wakefulness Test, up to the ceiling effect of 40 min, in both the single- and multiple-rising-dose studies. These findings indicate that OX2Rs remain functional despite long-term orexin loss in NT1. OX2R-selective agonists are a promising treatment for both NT1 and NT2.
Danavorexton, a selective orexin 2 receptor agonist, provides a symptomatic improvement in a narcolepsy mouse model
Pharmacol Biochem Behav 2022 Oct;220:173464.PMID:36108771DOI:10.1016/j.pbb.2022.173464.
Narcolepsy type 1 (NT1), caused by loss of orexin neurons, is a neurological disorder characterized by excessive daytime sleepiness, cataplexy, disrupted nighttime sleep, hypnagogic/hypnopompic hallucinations and sleep paralysis, as well as a high risk of obesity. Danavorexton (TAK-925) is a novel brain-penetrant orexin 2 receptor (OX2R)-selective agonist currently being evaluated in clinical trials for the treatment of hypersomnia disorders including NT1. Thus, detailed characterization of Danavorexton is critical for validating therapeutic potential of OX2R-selective agonists. Here, we report preclinical characteristics of Danavorexton as a therapeutic drug for NT1. Danavorexton showed rapid association/dissociation kinetics to OX2R. The activation mode of endogenous OX2R by Danavorexton and orexin peptide was very similar in an electrophysiological analysis. In orexin/ataxin-3 mice, a mouse model of NT1, Danavorexton promoted wakefulness, and ameliorated fragmentation of wakefulness during the active phase after both acute and repeated administration, suggesting a low risk of receptor desensitization. Electroencephalogram (EEG) power spectral analysis revealed that Danavorexton, but not modafinil, normalized dysregulated EEG power spectrum in orexin/ataxin-3 mice during the active phase. Finally, repeated administration of Danavorexton significantly suppressed the body weight gain in orexin/ataxin-3 mice. Danavorexton may have the potential to treat multiple symptoms of NT1. These preclinical findings, together with upcoming clinical observations of Danavorexton, could improve our understanding of the pathophysiology of NT1 and therapeutic potential of OX2R agonists.
Orexin 2 receptor-selective agonist Danavorexton (TAK-925) promotes wakefulness in non-human primates and healthy individuals
J Sleep Res 2023 Mar 19;e13878.PMID:36934366DOI:10.1111/jsr.13878.
The orexin 2 receptor-selective agonist Danavorexton (TAK-925) has been shown to produce wake-promoting effects in wild-type mice, narcolepsy-model mice, and individuals with narcolepsy type 1 and type 2. Here, we report wake-promoting effects of Danavorexton in non-human primates and healthy men during their sleep phase. Electroencephalogram analyses revealed that subcutaneous administration of Danavorexton significantly increased wakefulness in common marmosets (p < 0.05 at 0.1 mg kg-1 , and p < 0.001 at 1 mg kg-1 and 10 mg kg-1 ) and cynomolgus monkeys (p ≤ 0.05 at 1 mg kg-1 and 3 mg kg-1 ). In a phase 1b crossover, randomized, double-blind, placebo-controlled and active-controlled study in sleep-deprived healthy participants (ClinicalTrials.gov identifier: NCT03522506), modafinil 300 mg (used to demonstrate assay sensitivity) and continuous infusion of Danavorexton 44 mg and Danavorexton 112 mg showed statistically superior wake-promoting effects to placebo (n = 18). Measured using the Maintenance of Wakefulness Test, mean (standard deviation) sleep latencies during infusion of Danavorexton 44 mg, Danavorexton 112 mg and placebo were 21.4 (8.9), 31.8 (3.2) and 9.2 (6.4) min, respectively. Least-squares mean difference from placebo in average sleep latency was 16.8 min with Danavorexton 44 mg and 30.2 min with Danavorexton 112 mg (both p < 0.001). Karolinska Sleepiness Scale scores were statistically significantly lower (indicating decreased sleepiness) for participants receiving Danavorexton than for those receiving placebo during infusion (Danavorexton 44 mg, p = 0.010; Danavorexton 112 mg, p < 0.001). Together, these results indicate that an orexin 2 receptor agonist increases wakefulness in non-human primates and healthy individuals during their sleep phase.
Safety and pharmacodynamics of a single infusion of Danavorexton in adults with idiopathic hypersomnia
Sleep 2023 Mar 8;zsad049.PMID:36883238DOI:10.1093/sleep/zsad049.
Study objectives: Idiopathic hypersomnia (IH) is a chronic disorder characterized by excessive daytime sleepiness unexplained by another disorder or drug/medication use. Although the orexinergic system plays a role in sleep-wake regulation, orexin A levels in the cerebrospinal fluid are normal in people with IH. This phase 1b, randomized, placebo-controlled, crossover study aimed to investigate the safety, pharmacokinetics, and pharmacodynamics of Danavorexton, a small-molecule orexin-2 receptor agonist, in adults with IH. Methods: Adults with IH aged 18-75 years were randomized to one of two treatment sequences of single intravenous infusions of Danavorexton 112 mg and placebo. Pharmacodynamic endpoints included the maintenance of wakefulness test (MWT), the Karolinska Sleepiness Scale (KSS), and the psychomotor vigilance task (PVT). Adverse events were monitored throughout the study period. Results: Of 28 randomized participants, 12 (44.4%) had a treatment-emergent adverse event (TEAE) and 10 (37.0%) had a TEAE considered related to study drug, most of which were mild or moderate. Four participants (18.2%) had urinary TEAEs while receiving Danavorexton, all of which were mild in severity. There were no deaths or TEAEs leading to discontinuation. Improvements in MWT, KSS, and PVT scores were observed with Danavorexton compared to placebo. Following drug administration, a mean sleep latency of 40 minutes (maximum value) was observed during the MWT within 2 hours of Danavorexton infusion in most participants. Conclusions: A single infusion of Danavorexton improves subjective and objective excessive daytime sleepiness in people with IH with no serious TEAEs, indicating orexin-2 receptor agonists are promising treatments for IH.
TAK-994, a novel orally available brain-penetrant orexin 2 receptor-selective agonist, suppresses fragmentation of wakefulness and cataplexy-like episodes in mouse models of narcolepsy
J Pharmacol Exp Ther 2023 Mar 31;JPET-AR-2022-001449.PMID:37001988DOI:10.1124/jpet.122.001449.
Loss of orexin neurons is associated with narcolepsy type 1 (NT1), which is characterized by multiple symptoms including excessive daytime sleepiness and cataplexy. Orexin 2 receptor (OX2R) knockout (KO) mice, but not orexin 1 receptor (OX1R) KO mice, show narcolepsy-like phenotypes, thus OX2R agonists are potentially promising for treating NT1. In fact, in early proof-of-concept studies, intravenous infusion of Danavorexton, an OX2R-selective agonist, significantly increased wakefulness in individuals with NT1. However, Danavorexton has limited oral availability. Here, we report pharmacological characteristics of a novel OX2R agonist, TAK-994 [N-{(2S,3S)-1-(2-hydroxy-2-methylpropanoyl)-2-[(2,3',5'-trifluorobiphenyl-3-yl)methyl]pyrrolidin-3-yl}methanesulfonamide sesquihydrate]. TAK-994 activated recombinant human OX2R (EC50 value of 19 nM) with >700-fold selectivity against OX1R, and activated OX2R-downstream signaling similar to those by orexin peptides in vitro Oral administration of TAK-994 promoted wakefulness in normal mice, but not in OX2R KO mice. TAK-994 also ameliorated narcolepsy-like symptoms in two mouse models of narcolepsy: orexin/ataxin-3 mice and orexin-tTA;TetO diphtheria toxin A mice. The wake-promoting effects of TAK-994 in orexin/ataxin-3 mice were maintained after chronic dosing for 14 days. These data suggest that overall in vitro and in vivo properties, except oral availability, are very similar between TAK-994 and Danavorexton. Preclinical characteristics of TAK-994 shown here, together with upcoming clinical study results, can improve our understanding for orally available OX2R agonists as new therapeutic drugs for NT1 and other hypersomnia disorders. Significance Statement Narcolepsy type 1 (NT1) is caused by a loss of orexin neurons, and thus an orexin 2 receptor (OX2R) agonist is considered to address the underlying pathophysiology of NT1. Oral administration of TAK-994, a novel OX2R agonist, promoted wakefulness in normal mice, but not in OX2R knockout mice, and ameliorated fragmentation of wakefulness and cataplexy-like episodes in mouse models of narcolepsy. These findings indicate that TAK-994 is an orally available brain-penetrant OX2R-selective agonist with potential to improve narcolepsy-like symptoms.