TAK-915
目录号 : GC63209
TAK-915 是一种有效的，选择性的，可透过血脑屏障和口服活性的 PDE2A 抑制剂，IC50 为 0.61 nM。TAK-915 对 PDE2A 的选择性是 PDE1A 的 4100 倍以上。TAK-915 可用于神经精神疾病和神经退行性疾病的研究。
Cas No.:1476727-50-0
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
TAK-915 is a potent, selective, brain-penetrant and orally active phosphodiesterase 2A (PDE2A) inhibitor with an IC50 of 0.61 nM. TAK-915 is >4100-fold more selectivity for PDE2A than PDE1A. TAK-915 has the potential for neuropsychiatric and neurodegenerative disorders treatment[1][2].
TAK-915 (3 mg/kg; oral administration; daily; for 4 days; male F344 rats) treatment significantly reduces escape latency in aged rats in the Morris water maze task[2].TAK-915 (1, 3, and 10mg/kg, p.o.) dose-dependently attenuates the non-selective muscarinic antagonist scopolamine-induced memory deficits in rats[2]. Oral dosing of TAK-915 (compound 36) (3 or 10 mg/kg) in mice produces a dose-dependent increase in 3’,5’-cyclic guanosine monophosphate (cGMP) levels, with significant cGMP increases observed at a dose of 10 mg/kg[1].
[1]. Mikami S, et al. Discovery of Clinical Candidate N-((1S)-1-(3-Fluoro-4-(trifluoromethoxy)phenyl)-2-methoxyethyl)-7-methoxy-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxamide (TAK-915): A Highly Potent, Selective, and Brain-Penetrating Phosphodiesterase 2A Inhibitor for the Treatment of Cognitive Disorders. J Med Chem. 2017 Sep 28;60(18):7677-7702.
[2]. Nakashima M, et al. TAK-915, a phosphodiesterase 2A inhibitor, ameliorates the cognitive impairment associated with aging in rodent models. Behav Brain Res. 2019 Dec 30;376:112192.
| Cas No. | 1476727-50-0 | SDF | |
| 分子式 | C19H18F4N4O5 | 分子量 | 458.36 |
| 溶解度 | 储存条件 | ||
| 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 | 2.1817 mL | 10.9085 mL | 21.8169 mL |
| 5 mM | 0.4363 mL | 2.1817 mL | 4.3634 mL |
| 10 mM | 0.2182 mL | 1.0908 mL | 2.1817 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。
TAK-915, a phosphodiesterase 2A inhibitor, ameliorates the cognitive impairment associated with aging in rodent models
Behav Brain Res 2019 Dec 30;376:112192.PMID:31521738DOI:10.1016/j.bbr.2019.112192.
Changes in the cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) signaling are implicated in older people with dementia. Drugs that modulate the cAMP/cGMP levels in the brain might therefore provide new therapeutic options for the treatment of cognitive impairment in aging and elderly with dementia. Phosphodiesterase 2A (PDE2A), which is highly expressed in the forebrain, is one of the key phosphodiesterase enzymes that hydrolyze cAMP and cGMP. In this study, we investigated the effects of PDE2A inhibition on the cognitive functions associated with aging, such as spatial learning, episodic memory, and attention, in rats with a selective, brain penetrant PDE2A inhibitor, N-{(1S)-1-[3-fluoro-4-(trifluoromethoxy)phenyl]-2-methoxyethyl-7-methoxy-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxamide (TAK-915). Repeated treatment with TAK-915 (3 mg/kg/day, p.o. for 4 days) significantly reduced escape latency in aged rats in the Morris water maze task compared to the vehicle treatment. In the novel object recognition task, TAK-915 (1, 3, and 10 mg/kg, p.o.) dose-dependently attenuated the non-selective muscarinic antagonist scopolamine-induced memory deficits in rats. In addition, oral administration of TAK-915 at 10 mg/kg significantly improved the attentional performance in middle-aged, poorly performing rats in the 5-choice serial reaction time task. These findings suggest that PDE2A inhibition in the brain has the potential to ameliorate the age-related cognitive decline.
Phosphodiesterase 2A Inhibitor TAK-915 Ameliorates Cognitive Impairments and Social Withdrawal in N-Methyl-d-Aspartate Receptor Antagonist-Induced Rat Models of Schizophrenia
J Pharmacol Exp Ther 2018 Apr;365(1):179-188.PMID:29440309DOI:10.1124/jpet.117.245506.
The pathophysiology of schizophrenia has been associated with glutamatergic dysfunction. Modulation of the glutamatergic signaling pathway, including N-methyl-d-aspartate (NMDA) receptors, can provide a new therapeutic target for schizophrenia. Phosphodiesterase 2A (PDE2A) is highly expressed in the forebrain, and is a dual substrate enzyme that hydrolyzes both cAMP and cGMP, which play pivotal roles as intracellular second messengers downstream of NMDA receptors. Here we characterize the in vivo pharmacological profile of a selective and brain-penetrant PDE2A inhibitor, (N-{(1S)-1-[3-fluoro-4-(trifluoromethoxy)phenyl]-2-methoxyethyl}-7-methoxy-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxamide) (TAK-915) as a novel treatment of schizophrenia. Oral administration of TAK-915 at 3 and 10 mg/kg significantly increased cGMP levels in the frontal cortex, hippocampus, and striatum of rats. TAK-915 at 10 mg/kg significantly upregulated the phosphorylation of α-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid receptor subunit GluR1 in the rat hippocampus. TAK-915 at 3 and 10 mg/kg significantly attenuated episodic memory deficits induced by the NMDA receptor antagonist (+)-MK-801 hydrogen maleate (MK-801) in the rat passive avoidance test. TAK-915 at 10 mg/kg significantly attenuated working memory deficits induced by MK-801 in the rat radial arm maze test. Additionally, TAK-915 at 10 mg/kg prevented subchronic phencyclidine-induced social withdrawal in social interaction in rats. In contrast, TAK-915 did not produce antipsychotic-like activity; TAK-915 had little effect on MK-801- or methamphetamine-induced hyperlocomotion in rats. These results suggest that TAK-915 has a potential to ameliorate cognitive impairments and social withdrawal in schizophrenia.
Discovery of Clinical Candidate N-((1S)-1-(3-Fluoro-4-(trifluoromethoxy)phenyl)-2-methoxyethyl)-7-methoxy-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxamide (TAK-915): A Highly Potent, Selective, and Brain-Penetrating Phosphodiesterase 2A Inhibitor for the Treatment of Cognitive Disorders
J Med Chem 2017 Sep 28;60(18):7677-7702.PMID:28796496DOI:10.1021/acs.jmedchem.7b00807.
Phosphodiesterase (PDE) 2A inhibitors have emerged as a novel mechanism with potential therapeutic option to ameliorate cognitive dysfunction in schizophrenia or Alzheimer's disease through upregulation of cyclic nucleotides in the brain and thereby achieve potentiation of cyclic nucleotide signaling pathways. This article details the expedited optimization of our recently disclosed pyrazolo[1,5-a]pyrimidine lead compound 4b, leading to the discovery of clinical candidate 36 (TAK-915), which demonstrates an appropriate combination of potency, PDE selectivity, and favorable pharmacokinetic (PK) properties, including brain penetration. Successful identification of 36 was realized through application of structure-based drug design (SBDD) to further improve potency and PDE selectivity, coupled with prospective design focused on physicochemical properties to deliver brain penetration. Oral administration of 36 demonstrated significant elevation of 3',5'-cyclic guanosine monophosphate (cGMP) levels in mouse brains and improved cognitive performance in a novel object recognition task in rats. Consequently, compound 36 was advanced into human clinical trials.
Discovery of a Novel Series of Pyrazolo[1,5-a]pyrimidine-Based Phosphodiesterase 2A Inhibitors Structurally Different from N-((1S)-1-(3-Fluoro-4-(trifluoromethoxy)phenyl)-2-methoxyethyl)-7-methoxy-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxamide (TAK-915), for the Treatment of Cognitive Disorders
Chem Pharm Bull (Tokyo) 2017;65(11):1058-1077.PMID:29093293DOI:10.1248/cpb.c17-00564.
It has been hypothesized that selective inhibition of phosphodiesterase (PDE) 2A could potentially be a novel approach to treat cognitive impairment in neuropsychiatric and neurodegenerative disorders through augmentation of cyclic nucleotide signaling pathways in brain regions associated with learning and memory. Following our earlier work, this article describes a drug design strategy for a new series of lead compounds structurally distinct from our clinical candidate 2 (TAK-915), and subsequent medicinal chemistry efforts to optimize potency, selectivity over other PDE families, and other preclinical properties including in vitro phototoxicity and in vivo rat plasma clearance. These efforts resulted in the discovery of N-((1S)-2-hydroxy-2-methyl-1-(4-(trifluoromethoxy)phenyl)propyl)-6-methyl-5-(3-methyl-1H-1,2,4-triazol-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (20), which robustly increased 3',5'-cyclic guanosine monophosphate (cGMP) levels in the rat brain following an oral dose, and moreover, attenuated MK-801-induced episodic memory deficits in a passive avoidance task in rats. These data provide further support to the potential therapeutic utility of PDE2A inhibitors in enhancing cognitive performance.