Tryptophan hydroxylase
Tryptophan hydroxylase 1 (TPH1) (IC50 = 10 nM); Tryptophan hydroxylase 2 (TPH2) (IC50 = 190 nM) [1]
Tryptophan hydroxylase (TPH) (Ki = 7.6 nM for TPH1; Ki = 130 nM for TPH2) [2]

telotristat etiprate 的活性成分是 telotristat。称为telotristat etiprate 的乙酯前药被降解产生telotristat。一种称为 telotristat etiprate 的口服血清素合成抑制剂用于治疗类癌综合征[1]。

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重组人TPH1与Telotristat共同孵育时，血清素合成呈浓度依赖性抑制，IC50为10 nM；TPH2的抑制IC50为190 nM，对TPH1的选择性是TPH2的19倍[1]
在人类癌肿瘤细胞（NCI-H727）中，Telotristat处理（1-100 μM）以剂量依赖性方式降低血清素分泌，100 μM时最大抑制率达82%[1]
Telotristat以竞争性方式（相对于L-色氨酸）抑制TPH酶活性，Ki值分别为7.6 nM（TPH1）和130 nM（TPH2）[2]
浓度高达10 μM时，未观察到对其他芳香族氨基酸羟化酶（苯丙氨酸羟化酶、酪氨酸羟化酶）的显著抑制[2]

口服给药后，发现telotristat etiprate 的水平非常低。快速水解成活性部分telotristat是导致这些低水平的原因。半衰期在四到十二小时之间。当在两周内给予多次剂量时，telotristat 不会蓄积。 Telotristat 暴露量大致与剂量成正比[1]。

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在携带NCI-H727类癌肿瘤异种移植物的裸鼠中，口服给予Telotristat（30-300 mg/kg/天）14天，血浆血清素水平以剂量依赖性方式降低35-78%；最高剂量（300 mg/kg/天）还使肿瘤血清素含量降低65%[1]
在血清素诱导的腹泻大鼠模型中，口服Telotristat（10-100 mg/kg）显著降低腹泻频率，ED50为28 mg/kg[1]
在食蟹猴中，单次口服Telotristat（10-100 mg/kg）导致血浆药物浓度呈剂量比例增加，尿中5-羟吲哚乙酸（5-HIAA，血清素合成的替代标志物）排泄减少40-60%[2]

将重组人TPH1或TPH2与含有L-色氨酸和四氢生物蝶呤（BH4，辅因子）的反应缓冲液混合，加入不同浓度（0.1 nM-10 μM）的Telotristat，混合物在37°C孵育30分钟。通过加入高氯酸终止反应，采用高效液相色谱（HPLC）结合电化学检测定量生成的血清素含量，绘制抑制曲线计算IC50值[1]
测定Ki值时，在不同L-色氨酸浓度（0.5-10 μM）和固定Telotristat浓度下进行TPH酶活性测定。反应混合物在37°C孵育20分钟，通过荧光检测测量血清素生成量，使用Lineweaver-Burk图计算Ki值[2]

人NCI-H727类癌细胞在添加胎牛血清和抗生素的RPMI 1640培养基中培养，接种到24孔板后过夜贴壁。加入1-100 μM的Telotristat孵育24小时，收集培养上清液通过HPLC测量血清素水平。采用比色法评估细胞活力，确保观察到的效果并非由细胞毒性引起[1]
对经Telotristat（10 μM）处理6-24小时的NCI-H727细胞进行实时定量PCR（qPCR），提取总RNA并逆转录为cDNA，使用TPH1和GAPDH（管家基因）的特异性引物扩增。未观察到TPH1 mRNA水平显著变化，表明Telotristat直接抑制TPH1活性而非转录水平[1]

Dissolved in 15% cyclodextrin or 0.25% methylcellulose; 300 mg/kg; p.o.
Male C57BL/6 mice and male C57 albino mice.

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Nude mice (6-8 weeks old) were subcutaneously implanted with NCI-H727 tumor cells (5×106 cells/mouse). When tumors reached a volume of ~100 mm3, mice were randomized into treatment groups (n=6 per group) and administered Telotristat by oral gavage at doses of 30, 100, or 300 mg/kg/day, or vehicle control (0.5% methylcellulose), for 14 consecutive days. Blood samples were collected via retro-orbital puncture on days 0, 7, and 14 to measure plasma serotonin levels. At the end of the study, mice were euthanized, tumors were excised, and tumor serotonin content was quantified [1]
Male Sprague-Dawley rats were used to evaluate anti-diarrheal activity. Serotonin (10 mg/kg) was administered intraperitoneally to induce diarrhea. Telotristat was suspended in 0.5% methylcellulose and administered orally 1 hour before serotonin challenge at doses of 10, 30, or 100 mg/kg. Diarrhea frequency was recorded every 30 minutes for 4 hours [1]
Cynomolgus monkeys (3 males and 3 females per dose group) received single oral doses of Telotristat (10, 30, 100 mg/kg) or vehicle. Blood samples were collected at 0, 0.5, 1, 2, 4, 8, 12, and 24 hours post-dosing to determine plasma drug concentrations. Urine was collected over 24 hours to measure 5-HIAA excretion [2]

In cynomolgus monkeys, oral bioavailability of Telotristat was 45-55% after single doses of 10-100 mg/kg [2]
Plasma elimination half-life (t1/2) in monkeys was 3.2-4.5 hours [2]
Telotristat was widely distributed in tissues, with highest concentrations observed in the liver and kidneys [2]
Metabolic studies in human liver microsomes showed that Telotristat is metabolized primarily by CYP3A4, with minor contributions from CYP2C9 and CYP2C19 [2]
In rats, ~60% of the administered dose was excreted in feces and ~30% in urine within 72 hours, with unchanged drug accounting for ~25% of the fecal excretion [2]

Hepatotoxicity
In small clinical trials of telotristat in patients with neuroendocrine tumors and symptomatic diarrhea despite stable doses of somatostatin analogues, transient, asymptomatic and mild serum elevations of ALT occurred in 4% to 5% and of GGT in 6% to 9% of treated subjects. Apparent liver injury with jaundice was not observed in the several prelicensure clinical trials and has not been reported in the limited clinical experience with this agent since its approval.
Likelihood score: E (unlikely cause of clinically apparent liver injury).

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In a 28-day repeat-dose toxicity study in rats, Telotristat administered orally at doses up to 300 mg/kg/day did not cause significant changes in body weight, food consumption, or clinical chemistry parameters (alanine aminotransferase, aspartate aminotransferase, creatinine, blood urea nitrogen) [2]
No histopathological abnormalities were observed in the liver, kidneys, heart, or brain of treated rats [2]
Plasma protein binding of Telotristat in human plasma was 92-94% [2]
No significant inhibition of CYP enzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4) was observed at concentrations up to 10 μM in human liver microsomes [2]

[1]. Telotristat etiprate, a novel inhibitor of serotonin synthesis for the treatment of carcinoid syndrome. Clin. Invest. (Lond.) (2015) 5(5), 447–456.

[2]. US20080153852.

Telotristat is a phenylalanine derivative.
A tryptophan hydroxylase inhibitor. [Telotristat ethyl] (brand name Xermelo) is a prodrug of telotristat.
Telotristat is a Tryptophan Hydroxylase Inhibitor. The mechanism of action of telotristat is as a Tryptophan Hydroxylase Inhibitor.
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.
Telotristat is a tryptophan hydroxylase (TPH) inhibitor, with potential anti-serotonergic activity. Upon administration, telotristat binds to and inhibits the activity of TPH. This may result in a reduction in peripheral serotonin (5-HT) production and improvement of serotonin-mediated gastrointestinal effects such as severe diarrhea. TPH, the rate-limiting enzyme in serotonin biosynthesis, is overexpressed in carcinoid tumor cells.
See also: Telotristat Ethyl (active moiety of); Telotristat Etiprate (is active moiety of).

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Telotristat (LP-778902) is a novel, selective inhibitor of tryptophan hydroxylase (TPH), the rate-limiting enzyme in serotonin synthesis [1][2]
Carcinoid syndrome is characterized by excessive serotonin production by neuroendocrine tumors, leading to symptoms such as diarrhea, flushing, and wheezing [1]
Telotristat is being developed for the treatment of carcinoid syndrome, particularly for patients with diarrhea that is refractory to somatostatin analog therapy [1]
The selectivity of Telotristat for TPH1 (predominantly expressed in peripheral tissues) over TPH2 (expressed in the central nervous system) minimizes potential central nervous system-related side effects [1][2]

C25H22CLF3N6O3

546.93

546.139

C, 54.90; H, 4.05; Cl, 6.48; F, 10.42; N, 15.37; O, 8.78

1033805-28-5

Telotristat etiprate;1137608-69-5;Telotristat ethyl;1033805-22-9; 1033805-28-5 (acid); 1374745-52-4 (besilate)

25025298

Typically exists as White to light yellow solids at room temperature

1.50±0.1 g/cm3 (20 ºC 760 Torr), 计算值

5.791

142.17

3

11

8

38

790

2

ClC1C([H])=C([H])C(=C(C=1[H])N1C([H])=C([H])C(C([H])([H])[H])=N1)[C@]([H])(C(F)(F)F)OC1C([H])=C(C2C([H])=C([H])C(=C([H])C=2[H])C([H])([H])[C@@]([H])(C(=O)O[H])N([H])[H])N=C(N([H])[H])N=1

NCLGDOBQAWBXRA-PGRDOPGGSA-N

InChI=1S/C25H22ClF3N6O3/c1-13-8-9-35(34-13)20-11-16(26)6-7-17(20)22(25(27,28)29)38-21-12-19(32-24(31)33-21)15-4-2-14(3-5-15)10-18(30)23(36)37/h2-9,11-12,18,22H,10,30H2,1H3,(H,36,37)(H2,31,32,33)/t18-,22+/m0/s1

(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]propanoic acid

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

配方 1 中的溶解度: ≥ 2.5 mg/mL (4.57 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.5 mg/mL (4.57 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.5 mg/mL (4.57 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。