Velusetrag
(Synonyms: 1,2-二氢-N-[(3-内)-8-[(2R)-2-羟基-3-[甲基(甲磺酰基)氨基]丙基]-8-氮杂双环[3.2.1]辛-3-基]-1-(1-甲基乙基)-2-氧代-3-喹啉甲酰胺,TD-5108) 目录号 : GC63251
Velusetrag (TD-5108) 是一种具有口服活性，有效和选择性的血清素 5-HT4 受体 (5-HT4R) 激动剂，pKi 为 7.7。Velusetrag 对 5-HT2A 和 5-HT2B 受体没有亲和力 (Ki>10 μM)。Velusetrag 可用于胃肠道疾病和帕金森病的研究。
Cas No.:866933-46-2
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Velusetrag (TD-5108) is an orally active, potent and selective agonist of serotonin 5-HT4 receptor (5-HT4R), with a pKi of 7.7. Velusetrag exhibits no affinity (Ki>10 μM) for 5-HT2A and 5-HT2B receptors. Velusetrag can be used for the research of gastrointestinal diseases and Parkinson’s disease[1][2][3][4][5].
Velusetrag (10 pM-100 μM) concentration-dependently increases the cAMP in HEK-293 cells stably transfected with the h5-HT4(c) receptor, with a pEC50 of 8.3[1].Velusetrag (100 pM-1 μM) produces concentration-dependent contraction of the guinea pig colonic longitudinal muscle/myenteric plexus (LMMP), with a pEC50 of 7.9[1].Velusetrag (0.001-10 μM) produces a concentration-dependent relaxation of the carbachol (3 μM)-precontracted rat esophagus, with a pEC50 of 7.9[1].
Velusetrag (3 mg/kg; a single i.p.) significantly improves the facilitation of contextual fear extinction in PD mice[3].Velusetrag (3 mg/kg; a single i.p.) increases hippocampal cAMP levels in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice[3].Velusetrag (0.003-3 mg/kg; a single s.c.) increases colonic transit in a dose-dependent manner and reduces the time taken for excretion of the dye in guinea pigs[2].Velusetrag (0.003-1 mg/kg; a single i.v.) dose-dependently increases inter-crystal distance, consistent with relaxation of the oesophagus in rats[2].
[1]. Smith JAM, et, al. The in vitro pharmacological profile of TD-5108, a selective 5-HT(4) receptor agonist with high intrinsic activity. Naunyn Schmiedebergs Arch Pharmacol. 2008 Jul;378(1):125-37.
[2]. Beattie DT, et, al. The in vivo gastrointestinal activity of TD-5108, a selective 5-HT(4) receptor agonist with high intrinsic activity. Naunyn Schmiedebergs Arch Pharmacol. 2008 Jul;378(1):139-47.
[3]. Ishii T, et, al. Serotonin 5-HT 4 Receptor Agonists Improve Facilitation of Contextual Fear Extinction in an MPTP-Induced Mouse Model of Parkinson’s Disease. Int J Mol Sci. 2019 Oct 26;20(21):5340.
[4]. Kuo B, et al. Velusetrag accelerates gastric emptying in subjects with gastroparesis: a multicentre, double-blind, randomised, placebo-controlled, phase 2 study. Aliment Pharmacol Ther. 2021;53(10):1090-1097.
[5]. Goldberg M, et al. Clinical trial: the efficacy and tolerability of velusetrag, a selective 5-HT4 agonist with high intrinsic activity, in chronic idiopathic constipation - a 4-week, randomized, double-blind, placebo-controlled, dose-response study. Aliment Pharmacol Ther. 2010;32(9):1102-1112.
| Cas No. | 866933-46-2 | SDF | |
| 别名 | 1,2-二氢-N-[(3-内)-8-[(2R)-2-羟基-3-[甲基(甲磺酰基)氨基]丙基]-8-氮杂双环[3.2.1]辛-3-基]-1-(1-甲基乙基)-2-氧代-3-喹啉甲酰胺,TD-5108 | ||
| 分子式 | C25H36N4O5S | 分子量 | 504.64 |
| 溶解度 | DMSO : 100 mg/mL (198.16 mM; Need ultrasonic) | 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 | 1.9816 mL | 9.9081 mL | 19.8161 mL |
| 5 mM | 0.3963 mL | 1.9816 mL | 3.9632 mL |
| 10 mM | 0.1982 mL | 0.9908 mL | 1.9816 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 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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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。
Velusetrag for the treatment of chronic constipation
Expert Opin Investig Drugs 2016 Aug;25(8):985-90.PMID:27269187DOI:10.1080/13543784.2016.1195369.
Introduction: Chronic constipation is a frequent complaint in daily clinical practice. Notwithstanding the availability of numerous drugs, its treatment it is still unsatisfactory. However, new emerging treatments are in the pipeline and some drugs seem to be promising; among these Velusetrag, a selective 5-HT4 receptors agonist. Areas covered: An in depth Medline literature search was performed concerning topics related to the treatment of constipated patients with Velusetrag. In addition, abstracts concerning the topic were searched by hand in our libraries. Expert opinion: After analyzing the available data, the authors feel that Velusetrag may likely improve symptoms and the quality of life of chronically constipated subjects. However, additional data is needed to fully understand the safety and efficacy of Velusetrag, particularly in patients on long-term therapy. Thanks to the once-daily dosing and the pharmacologic properties, Velusetrag could be used as a single agent or in association with other drugs. In the future, this drug holds the potential to be an effective adjunct to the therapeutic armamentarium for chronic constipation.
New developments in the treatment of gastroparesis and functional dyspepsia
Curr Opin Pharmacol 2018 Dec;43:111-117.PMID:30245474DOI:10.1016/j.coph.2018.08.015.
Functional dyspepsia (FD) and gastroparesis are frequent causes of upper gastrointestinal symptoms such as postprandial fullness, early satiation, epigastric pain or burning, upper abdominal bloating, bothersome belching, nausea and vomiting. The underlying pathophysiological mechanisms are heterogeneous and involved mechanisms such as abnormal gastric motility (accommodation, emptying), visceral hypersensitivity, low grade mucosal inflammation and cellular changes in enteric nerves, muscle or interstitial cells of Cajal. Patient-reported outcomes for evaluating treatment efficacy in these conditions were recently developed and validated. Prokinetic agents, which enhance gastric motility, are used for treating both gastroparesis and FD. In FD, besides acid suppressive therapy and Helicobacter pylori eradication, neuromodulators and drugs that enhance gastric accommodation can be applied. In gastroparesis, anti-emetics may also provide symptom relief. Novel approaches under evaluation in these conditions are the fundus relaxing agents acotiamide and buspirone and the antidepressant mirtazapine in FD. For gastroparesis, recently studied agents include the prokinetic ghrelin agonist relamorelin, the prokinetic serotonergic agents Velusetrag and prucalopride, the anti-emetic aprepitant and per-endoscopic pyloric myotomy procedures.
Velusetrag accelerates gastric emptying in subjects with gastroparesis: a multicentre, double-blind, randomised, placebo-controlled, phase 2 study
Aliment Pharmacol Ther 2021 May;53(10):1090-1097.PMID:33811761DOI:10.1111/apt.16344.
Background: Gastroparesis is a serious gastrointestinal (GI) condition characterised by delayed gastric emptying (GE). Velusetrag-a potent, selective, pan-gastrointestinal 5-hydroxytryptamine type 4 receptor agonist-is under investigation for treatment of GI motility disorders including gastroparesis. Aims: To assess the efficacy and safety of Velusetrag for accelerating GE in subjects with diabetic or idiopathic gastroparesis. Methods: In this multicentre, randomised, double-blind, placebo-controlled, three-period fixed-sequence crossover phase 2 study, subjects with diabetic or idiopathic gastroparesis received oral Velusetrag (5, 15 or 30 mg) or placebo once daily for 7 days each. The primary outcome was proportion of subjects achieving ≥20% reduction in GE half-time (GE t1/2 ) from each treatment period baseline on day 7. Absolute and percent changes from baseline GE t1/2 were also assessed. GE was measured using a [13 C]-octanoate breath test. Safety was evaluated from treatment-emergent adverse events (TEAEs). Results: Thirty-four subjects (67.6% female; mean age, 46.3 years; 52.9% with diabetic gastroparesis) were included. Treatment with Velusetrag 30 mg significantly increased the proportion of subjects with ≥20% reduction from baseline GE t1/2 compared with placebo (52% vs 5%, P = 0.002), and GE t1/2 was numerically reduced following all three doses of Velusetrag relative to placebo treatment. Efficacy was similar between subjects with diabetic and idiopathic gastroparesis. Velusetrag treatment was generally well tolerated; most TEAEs were mild and related to GI transit acceleration. Conclusions: Velusetrag accelerates GE in subjects with diabetic or idiopathic gastroparesis and is generally well tolerated in this population (Clinicaltrials.gov NCT01718938).
Efficacy of drugs in chronic idiopathic constipation: a systematic review and network meta-analysis
Lancet Gastroenterol Hepatol 2019 Nov;4(11):831-844.PMID:31474542DOI:10.1016/S2468-1253(19)30246-8.
Background: There are several drugs available for the treatment of chronic idiopathic constipation, but their relative efficacy is unclear because there have been no head-to-head randomised controlled trials. We did a network meta-analysis to compare the efficacy of these therapies in patients with chronic idiopathic constipation. Methods: We searched Medline, Embase, Embase Classic, and the Cochrane Central Register of Controlled Trials for randomised controlled trials published from inception to week 3 June, 2019, to identify randomised controlled trials assessing the efficacy of drugs (osmotic or stimulant laxatives, elobixibat, linaclotide, lubiprostone, mizagliflozin, naronapride, plecanatide, prucalopride, tegaserod, tenapanor, or Velusetrag) in adults with chronic idiopathic constipation. Participants had to be treated for a minimum of 4 weeks, and we extracted data for all endpoints preferentially at 4 weeks, 12 weeks, or both. Trials included in the analysis reported a dichotomous assessment of overall response to therapy (response or no response to therapy). We pooled the data using a random effects model, and reported efficacy and safety of all treatments as a pooled relative risk (RR) with 95% CIs to summarise the effect of each comparison tested. To rank treatments, we used P-scores, which measure the extent of certainty that a treatment is better than another treatment, averaged over all competing treatments. Findings: We identified 33 eligible randomised controlled trials of drugs, comprising 17 214 patients. Based on an endpoint of failure to achieve three or more complete spontaneous bowel movements (CSBMs) per week, the stimulant diphenyl methane laxatives bisacodyl and sodium picosulfate, at a dose of 10 mg once daily, were ranked first at 4 weeks (RR 0·55, 95% CI 0·48-0·63, P-score 0·99), and prucalopride 2 mg once daily ranked first at 12 weeks (0·82, 0·78-0·86, P-score 0·96). When response to therapy was defined as falilure to achieve an increase of one or more CSBM per week from baseline, diphenyl methane laxatives at a dose of 10 mg once daily ranked first at 4 weeks (0·44, 0·37-0·54, P-score 0·99), with prucalopride 4 mg once daily ranked first at 12 weeks (0·74, 0·66-0·83, P-score 0·79), although linaclotide 290 μg once daily and prucalopride 2 mg once daily had similar efficacy (P-scores of 0·76 and 0·71, respectively). Bisacodyl ranked last in terms of safety for total number of adverse events and abdominal pain (P-score 0·08). Interpretation: Almost all drugs studied were superior to placebo, according to either failure to achieve three or more CSBMs per week or or failure to achieve an increase of one or more CSBM per week over baseline. Although diphenyl methane laxatives ranked first at 4 weeks, patients with milder symptoms might have been included in these trials. Prucalopride ranked first at 12 weeks, and many of the included trials recruited patients who previously did not respond to laxatives, suggesting that this drug is likely to be the most efficacious for patients with chronic idiopathic constipation. However, because treatment duration in most trials was 4-12 weeks, the long-term relative efficacy of these drugs is unknown. Funding: None.
Comparison of efficacy of pharmacological treatments for chronic idiopathic constipation: a systematic review and network meta-analysis
Gut 2017 Sep;66(9):1611-1622.PMID:27287486DOI:10.1136/gutjnl-2016-311835.
Objective: To compare efficacy of pharmacotherapies for chronic idiopathic constipation (CIC) based on comparisons to placebo using Bayesian network meta-analysis. Data sources: We conducted searches (inception to May 2015) of MEDLINE, EMBASE, Scopus and Cochrane Central, as well as original data from authors or drug companies for the medications used for CIC. Study selection: Phase IIB and phase III randomised, placebo-controlled trials (RCT) of ≥4 weeks' treatment for CIC in adults with Rome II or III criteria for functional constipation; trials included at least one of four end points. Data extraction and synthesis: Two investigators independently evaluated all full-text articles that met inclusion criteria and extracted data for primary and secondary end points, risk of bias and quality of evidence. Outcomes: Primary end points were ≥3 complete spontaneous bowel movements (CSBM)/week and increase over baseline by ≥1 CSBM/week. Secondary end points were change from baseline (Δb) in the number of SBM/week and Δb CSBM/week. Results: Twenty-one RCTs (9189 patients) met inclusion and end point criteria: 9 prucalopride, 3 lubiprostone, 3 linaclotide, 2 tegaserod, 1 each Velusetrag, elobixibat, bisacodyl and sodium picosulphate (NaP). All prespecified end points were unavailable in four polyethylene glycol studies. Bisacodyl, NaP, prucalopride and Velusetrag were superior to placebo for the ≥3 CSBM/week end point. No drug was superior at improving the primary end points on network meta-analysis. Bisacodyl appeared superior to the other drugs for the secondary end point, Δb in number of SBM/week. Conclusions: Current drugs for CIC show similar efficacy. Bisacodyl may be superior to prescription medications for Δb in the number of SBM/week in CIC.