TAK-041
(Synonyms: NBI-1065846) 目录号 : GC19811
TAK-041 是一流的、有效的、选择性的小分子 G 蛋白偶联受体 139 (GPR139) 激动剂，EC50 为 22 nM，正在开发用于治疗与精神分裂症相关的认知障碍和阴性症状。
Cas No.:1929519-13-0
Sample solution is provided at 25 µL, 10mM.
;)
,-1-7$$$37316672.jpg');)
;)
;)
$$$36806353.jpg');)
;33(7)%EF%BC%9A546-561$$$37156877.jpg');)
;)
;)
;)
%201124-1138.$$$35908550.jpg');)
%20766-780.$$$37100057.jpg');)
%20418-432.$$$36893736.jpg');)
%EF%BC%9A-240-255.$$$35108512.jpg');)
533-545$$$36543525.jpg');)
%201-13.$$$36600053.jpg');)
;)
Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| Cell experiment [1]: | |
|
Cell lines |
rat, dog, monkey, and human HepatoPac cells |
|
Preparation Method |
TAK-041 (2.00 mg) was dispensed into a 4-ml glass vial and stored frozen at -20°C until use. DMSO (509.8 µl) was added to the vial to generate a 10 mM stock solution.A 2-µl aliquot of a 10 µM stock solution of TAK-041 in DMSO was added to 998 µl of Krebs-Henseleit buffer (pH 7.4) to prepare a 20 µM working solution for the hepatocyte incubation. The hepatocyte incubations consisted of (final concentrations) 10 µM TAK-041.A 96-well plate was used for this study. The hepatocyte suspension incubations were initiated with the addition of an equal volume of TAK-041 in incubation buffer to hepatocytes in the plate (final cell concentration of 1 × 106 cells per milliliter, 100-µl total well volume). |
|
Reaction Conditions |
20 µM 0/2/4/24/48/168/336h |
|
Applications |
TAK-041 exhibited very low turnover in suspended cryopreserved hepatocyte suspensions, with no metabolites observed in human hepatocytes. Incubations conducted for up to 14 days in the HepatoPac model resulted in more robust metabolic turnover. The major biotransformation pathways of TAK-041 proceed via hydroxylation on the benzene ring fused to the oxotriazine moiety and subsequent sulfate, glucuronide, and glutathione conjugation reactions. The glutathione conjugate of TAK-041 undergoes further downstream metabolism to produce the cysteine S-conjugate, which then undergoes N-acetylation to mercapturic acid and/or conversion to β-lyase-derived thiol metabolites. The minor biotransformation pathways include novel ring closure and hydrolysis, hydroxylation, oxidative N-dealkylation, and subsequent reduction. The HepatoPac model shows a notable species difference in the rate and in the extent of metabolic pathways of TAK-041, with dogs having the fastest metabolic clearance and humans the slowest. |
| Animal experiment [2]: | |
|
Animal models |
C57BL/6 adult male mice |
|
Preparation Method |
Mice in the CSS and CON groups were allocated to three dose groups of TAK-041 suspension, namely 0, 1 or 3 mg/kg in 10 mL/kg vehicle p.o., administered at 60 min prior to test onset on each of the 6 test days ( per group). On the day after behavioral testing, mice were injected once more with their study dose and 60 min later, trunk blood was collected for determination of TAK-041 plasma exposur. |
|
Dosage form |
0.3, 1, 3 mg/kg po |
|
Applications |
TAK-041 does not alter tonic dopamine release in the nucleus accumbens.TAK-041 increases responding for a gustatory reward in minimally food-deprived mice.TAK-041 does not increase responding for reward in moderately food-deprived rats.TAK-041 does not alter food intake. |
|
References: [1]. Kamel A, Bowlin S, Hosea N, et al. In Vitro Metabolism of Slowly Cleared G Protein-Coupled Receptor 139 Agonist TAK-041 Using Rat, Dog, Monkey, and Human Hepatocyte Models (HepatoPac): Correlation with In Vivo Metabolism[J]. Drug Metabolism and Disposition, 2021, 49(2): 121-132. | |
TAK-041 is a first-in-class, potent, and selective small-molecule G protein-coupled receptor 139 (GPR139) agonist with an EC50 of 22 nM that is being developed for treating cognitive impairment and negative symptoms associated with schizophrenia. GPR139 is almost exclusively expressed in the central nervous system, and the highest expression of GPR139 receptors has been reported in the habenula[1], a brain region that has been shown to be critically involved in addiction, anxiety, and mood regulation[2,3] The role of orphan G protein-coupled receptors, including GPR139, in the pathophysiology of different diseases and disorders including anxiety, depression, schizophrenia, epilepsy, Alzheimer disease, Parkinson disease, and substance abuse disorders was recently discussed[4].
TAK-041 can block the suppression in neuronal firing brought about by MOR agonists [5]. The systems level, the interaction is indicated by the ability of MOR antagonists to counteract some of the behavioral impacts of GPR139 knockout[6].TAK-041 might suppress MOR activity. This is unlikely to contribute to the observed pro-motivational effects of TAK-041, though, because MOR knockout and antagonism decreased conditioned responding for food rewards[7-10].
TAK-041 increased the effort exerted to obtain sweet gustatory reward in mice that were only minimally food deprived. This effect of TAK-041 occurred both in control mice and in mice in which deficient effortful responding was induced by chronic social stress.
Tak-041 may be useful in the treatment of schizophrenia and other disorders associated with social and cognitive dysfunction . Pre-treatment with TAK-041 significantly attenuated the d-amphetamine-induced reduction in BPND in the a priori defined regions (putamen and ventral striatum: 26% and 18%, respectively). Findings suggest that TAK-041 enters the human brain and interacts with GPR139 to affect endogenous dopamine release. [11]. TAK-041 had a nearly linear pharmacokinetics profile, with rapid absorption and long half-life of 170-302 hours across all doses tested. Systemic exposure was 22-30% lower for patients with schizophrenia than for healthy volunteers. TAK-041 was generally well tolerated in healthy volunteers and adults with schizophrenia.
References:
[1].HITCHOCK S, Lam B, Monenschein H, et al. 4-oxo-3, 4-dihydro-1, 2, 3-benzotriazines as modulators of gpr139[P]. 2016-5-26.
[2].Fowler C D, Kenny P J. Habenular signaling in nicotine reinforcement[J]. Neuropsychopharmacology, 2012, 37(1): 306.
[3].Batalla A, Homberg J R, Lipina T V, et al. The role of the habenula in the transition from reward to misery in substance use and mood disorders[J]. Neuroscience & Biobehavioral Reviews, 2017, 80: 276-285.
[4].Alavi M S, Shamsizadeh A, Azhdari-Zarmehri H, et al. Orphan G protein-coupled receptors: The role in CNS disorders[J]. Biomedicine & Pharmacotherapy, 2018, 98: 222-232.
[5].Stoveken H M, Zucca S, Masuho I, et al. The orphan receptor GPR139 signals via Gq/11 to oppose opioid effects[J]. Journal of Biological Chemistry, 2020, 295(31): 10822-10830.
[6].Dao M, Stoveken H M, Cao Y, et al. The role of orphan receptor GPR139 in neuropsychiatric behavior[J]. Neuropsychopharmacology, 2022, 47(4): 902-913.
[7]Mena J D, Selleck R A, Baldo B A. Mu-opioid stimulation in rat prefrontal cortex engages hypothalamic orexin/hypocretin-containing neurons, and reveals dissociable roles of nucleus accumbens and hypothalamus in cortically driven feeding[J]. Journal of Neuroscience, 2013, 33(47): 18540-18552.
[8]Selleck R A, Lake C, Estrada V, et al. Endogenous opioid signaling in the medial prefrontal cortex is required for the expression of hunger-induced impulsive action[J]. Neuropsychopharmacology, 2015, 40(10): 2464-2474.
[9]Zhang M, Balmadrid C, Kelley A E. Nucleus accumbens opioid, GABaergic, and dopaminergic modulation of palatable food motivation: contrasting effects revealed by a progressive ratio study in the rat[J]. Behavioral neuroscience, 2003, 117(2): 202.
[10]Carlson H N, Murphy C, Pratt W E. Shifting motivational states: The effects of nucleus accumbens dopamine and opioid receptor activation on a modified effort-based choice task[J]. Behavioural Brain Research, 2021, 399: 112999.
[11]. Rabiner E A, Uz T, Mansur A, et al. Endogenous dopamine release in the human brain as a pharmacodynamic biomarker: evaluation of the new GPR139 agonist TAK-041 with [11C] PHNO PET[J]. Neuropsychopharmacology, 2022, 47(7): 1405-1412.
[12]. Yin W, Han D, Khudyakov P, et al. A phase 1 study to evaluate the safety, tolerability and pharmacokinetics of TAK‐041 in healthy participants and patients with stable schizophrenia[J]. British Journal of Clinical Pharmacology, 2022.
TAK-041 是一流的、有效的、选择性的小分子 G 蛋白偶联受体 139 (GPR139) 激动剂，EC50 为 22 nM，正在开发用于治疗与精神分裂症相关的认知障碍和阴性症状。 GPR139 几乎只在中枢神经系统中表达，据报道，在缰核[1] 中 GPR139 受体的表达最高，该大脑区域已被证明与成瘾、焦虑症密切相关和情绪调节[2,3] 孤儿 G 蛋白偶联受体（包括 GPR139）在不同疾病和障碍（包括焦虑症、抑郁症、精神分裂症、癫痫、阿尔茨海默病、帕金森病）的病理生理学中的作用最近讨论了疾病和药物滥用障碍[4]。
TAK-041 可以阻断 MOR 激动剂对神经元放电的抑制[5]。在系统层面，相互作用由 MOR 拮抗剂抵消 GPR139 敲除的一些行为影响的能力表明[6]。TAK-041 可能抑制 MOR 活性。不过，这不太可能有助于观察到 TAK-041 的促动机作用，因为 MOR 敲除和拮抗作用降低了对食物奖励的条件反应[7-10]。
TAK-041 增加了仅极少食物剥夺的小鼠获得甜味味觉奖赏的努力。 TAK-041 的这种作用在对照小鼠和由慢性社会压力诱导的努力反应不足的小鼠中均有发生。
Tak-041 可用于治疗精神分裂症和其他与社交和认知功能障碍相关的疾病。用 TAK-041 预处理显着减弱了先验定义区域（壳核和腹侧纹状体:分别为 26% 和 18%）中 d-苯丙胺诱导的 BPND 减少。研究结果表明，TAK-041 进入人脑并与 GPR139 相互作用以影响内源性多巴胺释放。 [11]. TAK-041 具有近乎线性的药代动力学特征，在所有测试剂量中具有快速吸收和 170-302 小时的长半衰期。精神分裂症患者的全身暴露量比健康志愿者低 22-30%。 TAK-041 在健康志愿者和患有精神分裂症的成年人中普遍耐受良好。
| Cas No. | 1929519-13-0 | SDF | |
| 别名 | NBI-1065846 | ||
| 分子式 | C₁₈H₁₅F₃N₄O₃ | 分子量 | 392.33 |
| 溶解度 | DMSO : 100 mg/mL (254.89 mM; Need ultrasonic) | 储存条件 | Store at -20℃ |
| 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。 |
||
| 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 | |||
 |
1 mg | 5 mg | 10 mg |
| 1 mM | 2.5489 mL | 12.7444 mL | 25.4887 mL |
| 5 mM | 0.5098 mL | 2.5489 mL | 5.0977 mL |
| 10 mM | 0.2549 mL | 1.2744 mL | 2.5489 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。
A phase 1 study to evaluate the safety, tolerability and pharmacokinetics of TAK-041 in healthy participants and patients with stable schizophrenia
Aims: TAK-041 (NBI-1065846), an orally available, investigational, small molecule agonist of GPR139, an orphan G-protein-coupled receptor, has shown promise in preclinical studies for the treatment of symptoms associated with schizophrenia. Here, we report the results from a phase 1 study to evaluate the safety, tolerability and pharmacokinetics of TAK-041 in healthy adults and exploratory efficacy assessment of TAK-041 as adjunctive therapy to antipsychotics in adults with stable schizophrenia (ClinicalTrials.gov: NCT02748694). Methods: The study comprised 4 parts: parts 1-3 were undertaken in healthy adults and part 4 in patients with stable schizophrenia. Part 1 was a single-rising-dose study, part 2 was a multiple-rising-dose study that assessed plasma exposure and accumulation, part 3 evaluated the bioavailability of tablet formulation versus oral suspension, and part 4 was a repeat multiple-dose study in patients with stable schizophrenia. Results: No serious adverse events were reported. TAK-041 had a nearly linear pharmacokinetics profile, with rapid absorption and long half-life of 170-302 hours across all doses tested. Bioavailability was similar between the tablet formulation and oral suspension, and no meaningful food effect was detected. Systemic exposure was 22-30% lower for patients with schizophrenia than for healthy volunteers. A potential signal of improvement was detected in the anxiety-depression scale of the Positive and Negative Syndrome Scale (P = .0002, not corrected for multiplicity) and the Temporal Experience of Pleasure Scale in patients with schizophrenia. Conclusion: TAK-041 was generally well tolerated in healthy volunteers and adults with schizophrenia. Further investigation of TAK-041 in individuals with schizophrenia is supported.
Discovery of TAK-041: a Potent and Selective GPR139 Agonist Explored for the Treatment of Negative Symptoms Associated with Schizophrenia
The orphan G-protein-coupled receptor GPR139 is highly expressed in the habenula, a small brain nucleus that has been linked to depression, schizophrenia (SCZ), and substance-use disorder. High-throughput screening and a medicinal chemistry structure-activity relationship strategy identified a novel series of potent and selective benzotriazinone-based GPR139 agonists. Herein, we describe the chemistry optimization that led to the discovery and validation of multiple potent and selective in vivo GPR139 agonist tool compounds, including our clinical candidate TAK-041, also known as NBI-1065846 (compound 56). The pharmacological characterization of these GPR139 agonists in vivo demonstrated GPR139-agonist-dependent modulation of habenula cell activity and revealed consistent in vivo efficacy to rescue social interaction deficits in the BALB/c mouse strain. The clinical GPR139 agonist TAK-041 is being explored as a novel drug to treat negative symptoms in SCZ.
In Vitro Metabolism of Slowly Cleared G Protein-Coupled Receptor 139 Agonist TAK-041 Using Rat, Dog, Monkey, and Human Hepatocyte Models (HepatoPac): Correlation with In Vivo Metabolism
Hepatic metabolism of low-clearance compound TAK-041 was studied in two different in vitro model systems using rat, dog, monkey, and human suspended cryopreserved hepatocytes and HepatoPac micropatterned coculture model primary hepatocytes. The aim of this work was to investigate the most appropriate system to assess the biotransformation of TAK-041, determine any notable species difference in the rate and in the extent of its metabolic pathways, and establish correlation with in vivo metabolism. TAK-041 exhibited very low turnover in suspended cryopreserved hepatocyte suspensions for all species, with no metabolites observed in human hepatocytes. However, incubations conducted for up to 14 days in the HepatoPac model resulted in more robust metabolic turnover. The major biotransformation pathways of TAK-041 proceed via hydroxylation on the benzene ring fused to the oxotriazine moiety and subsequent sulfate, glucuronide, and glutathione conjugation reactions. The glutathione conjugate of TAK-041 undergoes further downstream metabolism to produce the cysteine S-conjugate, which then undergoes N-acetylation to mercapturic acid and/or conversion to β-lyase-derived thiol metabolites. The minor biotransformation pathways include novel ring closure and hydrolysis, hydroxylation, oxidative N-dealkylation, and subsequent reduction. The HepatoPac model shows a notable species difference in the rate and in the extent of metabolic pathways of TAK-041, with dogs having the fastest metabolic clearance and humans the slowest. Furthermore, the model shows its suitability for establishing correlation with in vivo metabolism of low-turnover and extensively metabolized compounds such as TAK-041, displaying an extensive and unusual downstream sequential β-lyase-derived thiol metabolism in preclinical species and human. SIGNIFICANCE STATEMENT: This study investigated the most appropriate in vitro system to assess the biotransformation of the low-turnover and extensively metabolized compound TAK-041, determine any notable species difference in the rate and in the extent of its metabolic pathways, and establish correlation with in vivo metabolism. The HepatoPac model was identified and showed its suitability for species comparison and establishing correlation, with in vivo metabolism displaying an extensive and unusual downstream sequential β-lyase-derived thiol metabolism in preclinical species and human.
Endogenous dopamine release in the human brain as a pharmacodynamic biomarker: evaluation of the new GPR139 agonist TAK-041 with [11C]PHNO PET
The use of positron emission tomography (PET) in early-phase development of novel drugs targeting the central nervous system, is well established for the evaluation of brain penetration and target engagement. However, when novel targets are involved a suitable PET ligand is not always available. We demonstrate an alternative approach that evaluates the attenuation of amphetamine-induced synaptic dopamine release by a novel agonist of the orphan G-protein-coupled receptor GPR139 (TAK-041). GPR139 agonism is a novel candidate mechanism for the treatment of schizophrenia and other disorders associated with social and cognitive dysfunction. Ten healthy volunteers underwent [11C]PHNO PET at baseline, and twice after receiving an oral dose of d-amphetamine (0.5 mg/kg). One of the post-d-amphetamine scans for each subject was preceded by a single oral dose of TAK-041 (20 mg in five; 40 mg in the other five participants). D-amphetamine induced a significant decrease in [11C]PHNO binding potential relative to the non-displaceable component (BPND) in all regions examined (16-28%), consistent with increased synaptic dopamine release. Pre-treatment with TAK-041 significantly attenuated the d-amphetamine-induced reduction in BPND in the a priori defined regions (putamen and ventral striatum: 26% and 18%, respectively). The reduction in BPND was generally higher after the 40 mg than the 20 mg TAK-041 dose, with the difference between doses reaching statistical significance in the putamen. Our findings suggest that TAK-041 enters the human brain and interacts with GPR139 to affect endogenous dopamine release. [11C]PHNO PET is a practical method to detect the effects of novel drugs on the brain dopaminergic system in healthy volunteers, in the early stages of drug development.
Effects of GPR139 agonism on effort expenditure for food reward in rodent models: Evidence for pro-motivational actions
Apathy, deficiency of motivation including willingness to exert effort for reward, is a common symptom in many psychiatric and neurological disorders, including depression and schizophrenia. Despite improved understanding of the neurocircuitry and neurochemistry underlying normal and deficient motivation, there is still no approved pharmacological treatment for such a deficiency. GPR139 is an orphan G protein-coupled receptor expressed in brain regions which contribute to the neural circuitry that controls motivation including effortful responding for reward, typically sweet gustatory reward. The GPR139 agonist TAK-041 is currently under development for treatment of negative symptoms in schizophrenia which include apathy. To date, however, there are no published preclinical data regarding its potential effect on reward motivation or deficiencies thereof. Here we report in vitro evidence confirming that TAK-041 increases intracellular Ca2+ mobilization and has high selectivity for GPR139. In vivo, TAK-041 was brain penetrant and showed a favorable pharmacokinetic profile. It was without effect on extracellular dopamine concentration in the nucleus accumbens. In addition, TAK-041 did not alter the effort exerted to obtain sweet gustatory reward in rats that were moderately food deprived. By contrast, TAK-041 increased the effort exerted to obtain sweet gustatory reward in mice that were only minimally food deprived; furthermore, this effect of TAK-041 occurred both in control mice and in mice in which deficient effortful responding was induced by chronic social stress. Overall, this study provides preclinical evidence in support of GPR139 agonism as a molecular target mechanism for treatment of apathy.