LX1606 Hippurate (Telotristat etiprate)
(Synonyms: 特罗司他马尿酸盐; LX1606 Hippurate) 目录号 : GC10007
Telotristat etiprate 是一种乙酯前药，可在体内和体外水解为其活性部分 LP-778902。
Cas No.:1137608-69-5
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| Animal experiment [1]: | |
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Animal models |
Male C57BL/6 mice, male C57 albino mice |
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Preparation Method |
Two peripheral TPH inhibitors, LP-920540 and telotristat etiprate were given orally to mice. Effects were measured on 5-HT levels in the gut, blood and brain, 5-HT immunoreactivity in the ENS, gastrointestinal motility and severity of trinitrobenzene sulfonic acid (TNBS)-induced colitis. |
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Dosage form |
15, 50, 150, 300 mg/kg, Administered intragastrically |
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Applications |
Telotristat etiprate reduced 5-HT significantly in the gut and blood but not in the brain. Telotristat etiprate cannot decrease 5-HT immunoreactive neurons or fibres in the myenteric plexus or altered total gastrointestinal transit time, colonic motility or gastric emptying in mice. |
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References: [1]. Margolis, Kara Gross et al. Pharmacological reduction of mucosal but not neuronal serotonin opposes inflammation in mouse intestine. Gut vol. 63,6 (2014): 928-37. [2]. Lapuerta, P et al. Telotristat etiprate, a novel inhibitor of serotonin synthesis for the treatment of carcinoid syndrome. Clinical Investigation 2015 Vol.5 No.5 pp.447-456 ref.20 |
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Telotristat etiprate is an ethyl ester prodrug which is hydrolyzed to its active moiety LP-778902 both in vivo and in vitro. Systemic exposure of Telotristat etiprate is relatively low, as the hydrolysis to the active moiety is rapid. LP-778902 is a potent inhibitor of TPH with an in vivo IC50 of 0.028 μM.[2]
In normal mice, Telotristat etiprate (administered once daily for 4 days at doses of 15-300 mg/kg/day) was found to reduce serotonin levels throughout the gastro-intestinal tract. These reductions occurred in a dose-dependent fashion with maximal effects observed with doses of Telotristat etiprate ≥150 mg/kg. No significant change in brain serotonin or 5-hydroxyindoleacetic acid (5-HIAA, a serotonin metabolite) was observed. Similar findings were seen in Sprague-Dawley rats. [1, 2]
Gastrointestinal motility studies were conducted in rat using the charcoal meal teat. There was a significant dose-related delay in both gastrointestinal transit and gastric emptying, associated with a reduction in blood serotine levels and proximal colon serotonin. [2]
Telotristat etiprate and its active moiety LP-778902 were tested for their inhibition of two related enzymes, phenylalanine and tyrosine hydroxylase, as well as several cytochrome P450 isoenzymes. This demonstrated that Telotristat etiprate is a highly specific inhibitor of TPH. [2]
References:
[1]. Margolis, Kara Gross et al. Pharmacological reduction of mucosal but not neuronal serotonin opposes inflammation in mouse intestine. Gut vol. 63,6 (2014): 928-37.
[2]. Lapuerta, P et al. Telotristat etiprate, a novel inhibitor of serotonin synthesis for the treatment of carcinoid syndrome. Clinical Investigation 2015 Vol.5 No.5 pp.447-456 ref.20
Telotristat etiprate 是一种乙酯前药,可在体内和体外水解为其活性部分 LP-778902。 Telotristat etiprate 的全身暴露相对较低,因为对活性部分的水解是快速的。 LP-778902 是一种有效的 TPH 抑制剂,体内 IC50 为 0.028 μM。[2]
在正常小鼠中,发现 Telotristat etiprate（每天给药一次,剂量为 15-300 mg/kg/天,持续 4 天）可降低整个胃肠道的血清素水平。这些减低以剂量依赖方式发生,用 Telotristat etiprate ≥150 mg/kg 剂量观察到最大效应。未观察到脑血清素或 5-羟基吲哚乙酸（5-HIAA,一种血清素代谢物）的显着变化。在 Sprague-Dawley 大鼠中也观察到类似的发现。 [1, 2]
使用木炭餐奶嘴对大鼠进行了胃肠动力研究。胃肠道转运和胃排空均有显着的剂量相关延迟,这与血液血清素水平和近端结肠血清素的降低有关。 [2]
测试了 Telotristat etiprate 及其活性部分 LP-778902 对两种相关酶（苯丙氨酸和酪氨酸羟化酶）以及几种细胞色素 P450 同工酶的抑制作用。这表明 Telotristat etiprate 是一种高度特异性的 TPH 抑制剂。 [2]
| Cas No. | 1137608-69-5 | SDF | |
| 别名 | 特罗司他马尿酸盐; LX1606 Hippurate | ||
| 化学名 | 2-benzamidoacetic acid;ethyl (2S)-2-amino-3-[4-[2-amino-6-[(1R)-1-[4-chloro-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoroethoxy]pyrimidin-4-yl]phenyl]propanoate | ||
| Canonical SMILES | CCOC(=O)C(CC1=CC=C(C=C1)C2=CC(=NC(=N2)N)OC(C3=C(C=C(C=C3)Cl)N4C=CC(=N4)C)C(F)(F)F)N.C1=CC=C(C=C1)C(=O)NCC(=O)O | ||
| 分子式 | C36H35ClF3N7O6 | 分子量 | 754.17 |
| 溶解度 | DMF: 50 mg/ml,DMSO: 50 mg/ml,DMSO:PBS(pH 7.2) (1:2): 0.33 mg/ml,Ethanol: 5 mg/ml | 储存条件 | Store at -20°C, protected from light |
| 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 | 1.326 mL | 6.6298 mL | 13.2596 mL |
| 5 mM | 0.2652 mL | 1.326 mL | 2.6519 mL |
| 10 mM | 0.1326 mL | 0.663 mL | 1.326 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。
Telotristat
Review2018 Nov;68(6):471-487.PMID: 31643319DOI: 10.3322/caac.21493
Telotristat is an oral, small molecule inhibitor of tryptophan hydroxylase that is used in the treatment of symptoms of carcinoid syndrome. Telotristat is associated with modest rate of minor serum enzyme elevations during therapy but has not been linked to cases of clinically apparent liver injury.
Gastroenteropancreatic Neuroendocrine Tumors
CA Cancer J Clin2018 Nov;68(6):471-487.PMID: 30295930DOI: 10.3322/caac.21493
Neuroendocrine tumors (NETs) are heterogeneous malignancies arising from the diffuse neuroendocrine system. They frequently originate in the gastroenteropancreatic (GEP) tract and the bronchopulmonary tree, and their incidence has steadily increased in the last 3 decades. Fundamental biologic and genomic differences underlie the clinical heterogeneity of NETs, and distinct molecular features characterize NETs of different grades and different primary sites. Although surgery remains the cornerstone of treatment for localized tumors, systemic treatment options for patients with metastatic NETs have expanded considerably. Somatostatin analogs have demonstrated both antisecretory and antitumor efficacy. Peptide receptor radionuclide therapy with lutetium-177 dotatate (177 Lu-DOTATATE) has been approved for advanced GEP-NETs. The antitumor activity of everolimus has been demonstrated across a wide spectrum of NETs, and the antiangiogenic agent sunitinib has been approved for pancreatic NETs (pNETs). Chemotherapy with temozolomide and capecitabine has recently demonstrated an unprecedented prolongation of progression-free survival in a randomized trial of pNETs. Multiple retrospective series have reported the efficacy of liver-directed therapies both for palliating symptoms of hormone excess and for controlling tumor growth. Telotristat, an oral inhibitor of tryptophan hydroxylase, has been shown to reduce diarrhea in patients with carcinoid syndrome. Defining the therapeutic algorithm and identifying biomarkers predictive of response to treatments are among the main priorities for the next decade of research in the NET field.
Serotonin Pathway in Cancer
Int J Mol Sci2021 Jan 28;22(3):1268.PMID: 33525332DOI: 10.3390/ijms22031268
Serotonin (5-hydroxytryptamine, 5-HT) is a biogenic monoamine produced from the essential amino acid tryptophan. Serotonin's role as a neurotransmitter in the central nervous system and a motility mediator in the gastrointestinal tract has been well defined, and its function in tumorigenesis in various cancers (gliomas, carcinoids, and carcinomas) is being studied. Many studies have shown a potential stimulatory effect of serotonin on cancer cell proliferation, invasion, dissemination, and tumor angiogenesis. Although the underlying mechanism is complex, it is proposed that serotonin levels in the tumor and its interaction with specific receptor subtypes are associated with disease progression. This review article describes serotonin's role in cancer pathogenesis and the utility of the serotonin pathway as a potential therapeutic target in cancer treatment. Octreotide, an inhibitor of serotonin release, is used in well-differentiated neuroendocrine cancers, and the tryptophan hydroxylase (TPH) inhibitor, telotristat, is currently being investigated in clinical trials to treat patients with metastatic neuroendocrine tumors and advanced cholangiocarcinoma. Several in vitro studies have shown the anticancer effect of 5-HT receptor antagonists in various cancers such as prostate cancer, breast cancer, urinary bladder, colorectal cancer, carcinoid, and small-cell lung cancer. More in vivo studies are needed to assess serotonin's role in cancer and its potential use as an anticancer therapeutic target. Serotonin is also being evaluated for its immunoregulatory properties, and studies have shown its potential anti-inflammatory effect. Therefore, it would be of interest to explore the combination of serotonin antagonists with immunotherapy in the future.
Telotristat Ethyl: A Review in Carcinoid Syndrome Diarrhoea
Drugs2018 Jun;78(9):941-950.PMID: 29931594DOI: 10.1007/s40265-018-0935-1
Telotristat ethyl (Xermelo®), a first-in-class peripheral tryptophan hydroxylase (TPH) inhibitor, is approved to treat carcinoid syndrome diarrhoea in combination with somatostatin analogue (SSA) therapy in adults inadequately controlled by SSA therapy alone. Some neuroendocrine tumours secrete serotonin (5-HT) into the blood, resulting in frequent bowel movements (BMs) and other symptoms. Telotristat ethyl inhibits TPH, thereby reducing the production of 5-HT and improving carcinoid syndrome diarrhoea. In the 12-week placebo-controlled phase of randomized trials in patients with carcinoid syndrome diarrhoea (most of whom were receiving SSA therapy), the addition of oral telotristat ethyl 250 three times daily provided significant reductions in the frequency of BMs and levels of urinary 5-hydroxyindolacetic acid (u5-HIAA; a metabolite of 5-HT) relative to placebo. Telotristat ethyl 250 mg three times daily was well tolerated, with the proportion of patients reporting at least one treatment-emergent adverse event being similar to that with placebo. With regard to adverse events of special interest, relative to placebo, telotristat ethyl had a comparable incidence of depression-related symptoms, a somewhat higher incidence of gastrointestinal (GI) disorders and a higher incidence of elevated hepatic enzyme levels.
Telotristat etiprate for carcinoid syndrome: a single-arm, multicenter trial
J Clin Endocrinol Metab2015 Apr;100(4):1511-9.PMID: 25636046DOI: 10.1210/jc.2014-2247
Context: Carcinoid syndrome (CS) is associated with elevated serotonin, diarrhea, flushing, and increased risk of valvular heart disease. Many patients respond to somatostatin analogs initially, but response diminishes in most patients. Additional options are needed.
Objective: To assess whether telotristat etiprate (TE) can reduce gastrointestinal symptoms in CS and reduce urinary 5-hydroxyindoleacetic acid (u5-HIAA; a biomarker of serotonin).
Design: A prospective, exploratory, dose-escalating 12-week, open-label, multicenter study of TE with efficacy and safety analyses.
Setting: A multicenter study.
Patients: Eligible patients had metastatic, well-differentiated, neuroendocrine tumors and CS with ≥ four bowel movements (BMs) per day. Somatostatin analog use was allowed.
Interventions: TE, a novel oral inhibitor of peripheral serotonin synthesis.
Main outcome measures: Primary: safety. Secondary: daily BMs, stool form, and u5-HIAA.
Results: Fifteen patients were enrolled, and 14 completed the treatment period. All patients experienced reductions in BMs per day (mean decrease, 43.5%). A 74.2% mean reduction in u5-HIAA, the main metabolite of serotonin, was observed, with generally greater reductions in patients with greater reductions in BMs per day. Nine patients (75%) reported "adequate relief" of gastrointestinal symptoms at 12 weeks, compared with two (17%) at baseline. Stool form and flushing also improved. Adverse events were mostly gastrointestinal (n = 10; 67%), consistent with underlying illness; three adverse events were serious (abdominal pain, diarrhea, and gastroenteritis) but were judged unrelated.
Conclusion: TE was generally safe and well tolerated. Patients experienced substantial improvement in CS and reductions in u5-HIAA, consistent with the mechanism of action of TE. These results support further evaluation in phase 3 studies.