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Purity: ≥98%
Telotristat (formerly known as LP-778902; LP778902) is the active metabolite of LX1606 (LX-1606; Telotristat etiprate) which is an orally bioavailable and small-molecule inhibitor of tryptophan hydroxylase (TPH, IC50 = 0.028 μM) with potential antiserotonergic activity. Telotristat has activity in controlling diarrhea associated with carcinoid syndrome. Telotristat acts by inhibiting the enzyme tryptophan hydoxylase (TPH) and reduces serotonin production both inside and outside the GI tract without affecting brain serotonin levels. Blocking peripheral serotonin synthesis by telotristat reduces severity of both chemical- and infection-induced intestinal inflammation.
| Targets |
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] |
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| ln Vitro |
The active component of telotristat etiprate is telotristat. An ethyl ester prodrug called telotristat etiprate is degraded to produce telotristat. An oral serotonin synthesis inhibitor called telotristat etiprate is used to treat carcinoid syndrome[1].
Incubation of recombinant human TPH1 with Telotristat resulted in concentration-dependent inhibition of serotonin synthesis, with an IC50 of 10 nM; TPH2 was inhibited with an IC50 of 190 nM, showing 19-fold selectivity for TPH1 over TPH2 [1] In human carcinoid tumor cells (NCI-H727), Telotristat treatment (1-100 μM) reduced serotonin secretion in a dose-dependent manner, with a maximum inhibition of 82% at 100 μM [1] Telotristat inhibited TPH enzyme activity in a competitive manner with respect to L-tryptophan, with Ki values of 7.6 nM (TPH1) and 130 nM (TPH2) [2] No significant inhibition of other aromatic amino acid hydroxylases (phenylalanine hydroxylase, tyrosine hydroxylase) was observed at concentrations up to 10 μM [2] |
| ln Vivo |
Following oral administration, very low levels of telotristat etiprate are found. The quick hydrolysis into the active moiety telotristat is the cause of these low levels. The half-life is between four and twelve hours. When multiple doses are administered over the course of two weeks, there is no accumulation of telotristat. Telotristat exposure is roughly dose proportional[1].
In nude mice bearing NCI-H727 carcinoid tumor xenografts, oral administration of Telotristat (30-300 mg/kg/day) for 14 days reduced plasma serotonin levels by 35-78% in a dose-dependent manner; the highest dose (300 mg/kg/day) also decreased tumor serotonin content by 65% [1] In a rat model of serotonin-induced diarrhea, oral Telotristat (10-100 mg/kg) significantly reduced diarrhea frequency, with an ED50 of 28 mg/kg [1] In cynomolgus monkeys, single oral doses of Telotristat (10-100 mg/kg) resulted in dose-proportional increases in plasma drug concentrations, and a 40-60% reduction in urinary 5-hydroxyindoleacetic acid (5-HIAA) excretion (a surrogate marker of serotonin synthesis) [2] |
| Enzyme Assay |
Recombinant human TPH1 or TPH2 was mixed with reaction buffer containing L-tryptophan and tetrahydrobiopterin (BH4) as cofactor. Telotristat was added at various concentrations (0.1 nM-10 μM), and the mixture was incubated at 37°C for 30 minutes. The reaction was terminated by addition of perchloric acid, and the amount of serotonin produced was quantified using high-performance liquid chromatography (HPLC) with electrochemical detection. Inhibition curves were generated to calculate IC50 values [1]
For Ki determination, TPH enzyme assays were performed with varying concentrations of L-tryptophan (0.5-10 μM) and fixed concentrations of Telotristat. The reaction mixture was incubated at 37°C for 20 minutes, and serotonin formation was measured by fluorescence detection. Ki values were calculated using Lineweaver-Burk plots [2] |
| Cell Assay |
NCI-H727 human carcinoid cells were cultured in RPMI 1640 medium supplemented with fetal bovine serum and antibiotics. Cells were seeded into 24-well plates and allowed to adhere overnight. Telotristat was added at concentrations ranging from 1 to 100 μM, and cells were incubated for 24 hours. Culture supernatants were collected, and serotonin levels were measured by HPLC. Cell viability was assessed using a colorimetric assay to ensure that the observed effects were not due to cytotoxicity [1]
Quantitative real-time PCR (qPCR) was performed to evaluate TPH1 mRNA expression in NCI-H727 cells treated with Telotristat (10 μM) for 6-24 hours. Total RNA was isolated, reverse-transcribed to cDNA, and amplified using specific primers for TPH1 and GAPDH (housekeeping gene). No significant change in TPH1 mRNA levels was observed, indicating that Telotristat inhibits TPH1 activity directly rather than transcriptionally [1] |
| Animal Protocol |
Dissolved in 15% cyclodextrin or 0.25% methylcellulose; 300 mg/kg; p.o.
Male C57BL/6 mice and male C57 albino mice. 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] |
| ADME/Pharmacokinetics |
In cynomolgus monkeys, the bioavailability of a single oral dose of 10–100 mg/kg of Telotristat is 45–55% [2]. The plasma elimination half-life (t1/2) of Telotristat in monkeys is 3.2–4.5 hours [2]. Telotristat is widely distributed in various tissues, with the highest concentrations in the liver and kidneys [2]. Metabolic studies in human liver microsomes indicate that Telotristat is primarily metabolized by CYP3A4, with smaller contributions from CYP2C9 and CYP2C19 [2]. In rats, approximately 60% of the administered dose is excreted in feces within 72 hours, and approximately 30% is excreted in urine, with approximately 25% of the fecal excretion being the unchanged drug [2].
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| Toxicity/Toxicokinetics |
Hepatotoxicity
In small clinical trials of patients with neuroendocrine tumors who experienced symptomatic diarrhea despite taking stable doses of somatostatin analogues, transient, asymptomatic, and mild serum ALT elevations occurred in 4% to 5% of treated subjects, and serum GGT elevations occurred in 6% to 9% of treated subjects. No significant liver injury with jaundice has been observed in multiple premarketing clinical trials, nor has it been reported in limited clinical experience since the drug's approval. Probability score: E (unlikely to be the cause of clinically significant liver injury). In a 28-day repeated-dose toxicity study in rats, oral doses of up to 300 mg/kg/day of Telotristat did not cause significant changes in body weight, food consumption, or clinical chemical 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]. Telotristat has a plasma protein binding rate of 92-94% in human plasma[2]. No inhibition of CYP enzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 at concentrations up to 10 μM observed in human liver microsomes[2] |
| References | |
| Additional Infomation |
Telotristat is a phenylalanine derivative belonging to the class of tryptophan hydroxylase inhibitors. [Telotristat ethyl] (trade name Xermelo) is a prodrug of Telotristat. Telotristat is a tryptophan hydroxylase inhibitor. Its mechanism of action is as a tryptophan hydroxylase inhibitor. Telotristat is an orally administered small molecule tryptophan hydroxylase inhibitor used to treat symptoms of carcinoid syndrome. Mild elevations in serum enzymes may occur during Telotristat treatment, but have not been found to be associated with clinically significant liver injury. Telotristat is a tryptophan hydroxylase (TPH) inhibitor with potential antiserotonin activity. After administration, Telotristat binds to TPH and inhibits its activity. This may lead to reduced peripheral serotonin (5-HT) production and improved 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); Telotristat ethyl (its active ingredient). Telotristat (LP-778902) is a novel selective tryptophan hydroxylase (TPH) inhibitor, TPH being the rate-limiting enzyme in serotonin synthesis [1][2] Carcinoid syndrome is characterized by neuroendocrine tumors overproducing serotonin, leading to symptoms such as diarrhea, flushing, and wheezing [1] Telotristat is being developed for the treatment of carcinoid syndrome, particularly in patients with diarrhea unresponsive to somatostatin analogues [1] Telotristat has higher selectivity for TPH1 (primarily expressed in peripheral tissues) than for TPH2 (expressed in the central nervous system), thereby minimizing potential central nervous system-related side effects [1][2] |
| Molecular Formula |
C25H22CLF3N6O3
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| Molecular Weight |
546.93
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| Exact Mass |
546.139
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| Elemental Analysis |
C, 54.90; H, 4.05; Cl, 6.48; F, 10.42; N, 15.37; O, 8.78
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| CAS # |
1033805-28-5
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| Related CAS # |
Telotristat etiprate;1137608-69-5;Telotristat ethyl;1033805-22-9; 1033805-28-5 (acid); 1374745-52-4 (besilate)
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| PubChem CID |
25025298
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| Appearance |
Typically exists as White to light yellow solids at room temperature
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| Density |
1.50±0.1 g/cm3 (20 ºC 760 Torr), 计算值
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| LogP |
5.791
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
11
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
38
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| Complexity |
790
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| Defined Atom Stereocenter Count |
2
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| SMILES |
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
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| InChi Key |
NCLGDOBQAWBXRA-PGRDOPGGSA-N
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| InChi Code |
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
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| Chemical Name |
(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
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.57 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (4.57 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (4.57 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8284 mL | 9.1419 mL | 18.2839 mL | |
| 5 mM | 0.3657 mL | 1.8284 mL | 3.6568 mL | |
| 10 mM | 0.1828 mL | 0.9142 mL | 1.8284 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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