Usmarapride
(Synonyms: SUVN-D4010) 目录号 : GC64080
Usmarapride (SUVN-D4010) 是一种有效的、具有选择性、口服活性和可透过血脑屏障的 5-HT4 受体部分激动剂 (EC50=nM)。Usmarapride (SUVN-D4010) 可用于阿尔茨海默病相关认知缺陷的研究。
Cas No.:1428862-33-2
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
Usmarapride (SUVN-D4010) is a potent, selective, orally active and brain penetrant 5-HT4 receptor partial agonist (EC50=44 nM). Usmarapride (SUVN-D4010) can be used for the research of cognitive deficits associated with Alzheimer’s disease[1].
Usmarapride (SUVN-D4010) (1-3 mg/kg; p.o.; Male Wistar rats 10-12 weeks old) attenuates the long-term memory deficits in object recognition test (ORT)[1].Usmarapride (1, 3, and 10 mg/kg; p.o.) significantly reverses the scopolamine-induced amnesia[1]. Usmarapride shows a statistically significant effect at 3.0 mg/kg on both exploration time and recognition index[1].Usmarapride (SUVN-D4010) shows good oral exposures, good bioavailability, and good brain exposures in rats[1].Pharmacokinetic of Usmarapride in Rats[1](3.0 mg/kg for p.o. dosing; 1.0 mg/kg for i.v.) F% Cmax (ng/mL) AUC (ng.hr/mL) t1/2 (h) Vdss (L/kg) CL (mLg/min/kg) 34 360 709 1.7 8.0 76
[1]. Nirogi, Ramakrishna; Mohammed, Abdul Rasheed; Yarlgadda, Suresh; Ravella, Srinivasa Rao; Shinde, Anil Karbhari; Kambhampati, Ramasastri; Roayalley, Praveen Kumar; Jayarajan, Pradeep; Bhyrapuneni, Gopinadh; Patnala, Sriramachandra Murthy; et al. Preparation of heteroaryl compounds as 5-HT4 receptor ligands.WO2013042135A1
| Cas No. | 1428862-33-2 | SDF | Download SDF |
| 别名 | SUVN-D4010 | ||
| 分子式 | C23H31N5O6 | 分子量 | 473.52 |
| 溶解度 | 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 | 2.1118 mL | 10.5592 mL | 21.1184 mL |
| 5 mM | 0.4224 mL | 2.1118 mL | 4.2237 mL |
| 10 mM | 0.2112 mL | 1.0559 mL | 2.1118 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。
Usmarapride (SUVN-D4010), a 5-HT4 receptor partial agonist for the potential treatment of Alzheimer's disease: Behavioural, neurochemical and pharmacological profiling
Eur J Pharmacol 2023 May 15;947:175625.PMID:36997046DOI:10.1016/j.ejphar.2023.175625.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder which affects cognitive functions with negative impact on day to day activities and an ultimate loss of independent living. Current standard of care (SOC) for AD, viz. donepezil, rivastigmine, galantamine, memantine etc. either alone or in combination show modest efficacy without changing the course of the disease. On prolonged treatment, side effects are more common with an eventual loss of efficacy. Aducanumab, a monoclonal antibody is a disease modifying therapeutic agent targeting the toxic amyloid beta (Aβ) proteins for its clearance. However, it is found to have only modest efficacy in AD patients and its approval by FDA is controversial. Alternate, effective and safe therapeutics are need of the hour, as AD cases are expected to be doubled by 2050. Recently, 5-HT4 receptors have been envisioned as target for alleviating AD associated cognitive impairment with potential disease modifying ability impacting disease progression. Usmarapride is a 5-HT4 receptor partial agonist, being developed for the possible treatment of AD with symptomatic and disease modifying potential. Usmarapride demonstrated promising effects in ameliorating cognitive deficits in diverse animal models of episodic, working, social, and emotional memories. Usmarapride produced elevation in cortical acetylcholine levels in rats. Furthermore, Usmarapride increased levels of soluble amyloid precursor protein alpha, a potential mechanism to reverse toxic Aβ peptide pathology. Usmarapride also potentiated the pharmacological effects of donepezil in animal models. To conclude, Usmarapride may be a promising intervention for alleviating the cognitive dysfunction in AD patients with disease modifying potential.
Discovery and Preclinical Characterization of Usmarapride (SUVN-D4010): A Potent, Selective 5-HT4 Receptor Partial Agonist for the Treatment of Cognitive Deficits Associated with Alzheimer's Disease
J Med Chem 2021 Aug 12;64(15):10641-10665.PMID:34251799DOI:10.1021/acs.jmedchem.1c00703.
A series of oxadiazole derivatives were synthesized and evaluated as 5-hydroxytryptamine-4 receptor (5-HT4R) partial agonists for the treatment of cognitive deficits associated with Alzheimer's disease. Starting from a reported 5-HT4R antagonist, a systematic structure-activity relationship was conducted, which led to the discovery of potent and selective 5-HT4R partial agonist 1-isopropyl-3-{5-[1-(3-methoxypropyl) piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate (Usmarapride, 12l). It showed balanced physicochemical-pharmacokinetic properties with robust nonclinical efficacy in cognition models. It also showed disease-modifying potential, as it increased neuroprotective soluble amyloid precursor protein alpha levels, and dose-dependent target engagement and correlation of efficacy with oral exposures. Phase 1 clinical studies have been completed and projected efficacious concentration was achieved without any major safety concerns. Phase 2 enabling long-term safety studies have been completed with no concerns for further development.
A selective and accurate liquid chromatography-tandem mass spectrometry method for the quantitation of the novel 5-HT4 receptor partial agonist SUVN-D4010 (Usmarapride) in human plasma and urine
J Pharm Biomed Anal 2022 Mar 20;211:114617.PMID:35124447DOI:10.1016/j.jpba.2022.114617.
Liquid chromatography and the tandem mass spectrometry method to quantitate SUVN-D4010 (Usmarapride) in human plasma and urine have been developed and fully validated in compliance with regulatory guidelines. The sample preparation technique is simple and rapid consisting of acetonitrile precipitation followed by dilution of supernatant with a compatible solvent. Chromatographic separation was achieved on an X-Bridge C18 (2.1×50 mm, 3.5 µm) column using 0.1% v/v ammonium hydroxide and acetonitrile as mobile phase components, delivered at a flow rate of 0.75 mL min-1. Electrospray Ionization technique in positive mode was used for mass spectrometric detection. Selective reaction monitoring (SRM) transitions of m/z 384.2 → 352.1 for SUVN-D4010 and m/z 388.2 → 356.1 for SUVN-D4010-d4 were used for quantitation. Calibration curves for SUVN-D4010 were linear across the concentration range of 0.3-300 ng mL-1 in human plasma and 5.00-5000 ng mL-1 in human urine. The method generated results with acceptable accuracy (± 9.0%), precision (%CV, ≤8.7), and mean extraction recovery (≥93.4%) with negligible matrix effect in both plasma and urine. SUVN-D4010 was found to be stable in human plasma and urine at the defined storage conditions. The validated method was successfully applied to quantitate SUVN-D4010 in human plasma and urine from a clinical first-in-human study conducted to evaluate its safety, tolerability, and pharmacokinetics in healthy adults.