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2mg |
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5mg |
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10mg |
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25mg |
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50mg |
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100mg |
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250mg |
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Purity: ≥98%
Telotristat ethyl (formerly LX-1032; LX-1606; LX-1032; LX-1606; trade name: Xermelo), the ethyl ester prodrug form of Telotristat, is an orally bioavailable tryptophan hydroxylase (TPH) inhibitor (IC50 = 0.028 μM) with antiserotonergic and anti-diarrhea activity. As of 2017, Telotristat ethyl has been approved to treat carcinoid syndrome diarrhea. 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
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ln Vitro |
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ln Vivo |
The peripheral but not the brain of the mice is less serotonin-containing when telotristat ethyl (15, 50, 150, 300 mg/kg, po, qd) is administered. Telotristat ethyl (200 mg/kg po, qd) significantly protects against TNBS-induced elevation in blood neutrophil counts in a rat model of inflammatory bowel disease. The mouse IBD model is protected by telotristat ethyl (200 mg/kg po, qd), as shown by histopathological evaluation[1]. In the jejunum, telotristat ethyl (15, 50, 150, and 300 mg/kg) depletes 5-HT, but not in the brain. However, neither the constitutive gastrointestinal motility in mice nor the depletion of enteric neuronal serotonin (5-HT) are caused by telotristat ethyl (200 mg/kg, po). The severity of colitis caused by trinitrobenzene sulfonic acid (TNBS) is lessened by telotristat ethyl (200 mg/kg)[2].
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Animal Protocol |
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References |
[1]. LX1606 (aka LX1032), a Novel Inhibitor of Serotonin Synthesis, Alleviates Development of Inflammatory Bowel Disease in a Preclinical Model. (http://assets.cureus.com/uploads/poster/file/46/d.pdf)
[2]. Pharmacological reduction of mucosal but not neuronal serotonin opposes inflammation in mouse intestine. Gut, 2014 Jun;63(6):928-37. |
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Additional Infomation |
Dysfunctional signaling by the immunoendocrine mediator serotonin (5-HT) may play an important role in the pathophysiology of inflammatory bowel disease (IBD).1,2 Mucosal inflammatory lesions are accompanied by alterations in 5-HT producing enterochromaffin cells (EC). The first step of 5-HT synthesis in the gut is catalyzed by tryptophan hydroxylase 1 (TPH1), prominently expressed in EC. Experience with both TPH1 knockout mice and the TPH inhibitor para-chlorophenylalanine illustrates that reduction in 5-HT synthesis alleviates inflammatory damage in mouse models of IBD.1,2 These data, along with the reported association between 5-HT production and various gastrointestinal (GI) diseases, support the hypothesis that lowering 5-HT production could provide a benefit for IBD patients. We have developed TPH inhibitors that deplete serotonin in the periphery but not in the central nervous system (CNS).3,4 Such agents have potential therapeutic applications where elevated serotonin activity is thought to play a role. We reported the discovery of the TPH inhibitor LX1606 (aka LX1032), which reduced peripheral 5-HT production in preclinical and human studies. We now evaluate the efficacy of LX1606 in an experimental IBD model with the goal of developing a new therapeutic approach for IBD. [1]
Telotristat ethyl is a prodrug of telotristat that was approved by the FDA in March 2017 as Xermelo. It was previously referred to as telotristat etiprate, the hippurate salt form; however, the FDA recommends the use of the name of the neutral form rather than that of the salt. Currently, telotristat ethyl is used to treat carcinoid syndrome diarrhea from neuroendocrine tumors that are inadequately controlled by short-acting somatostatin analog (SSA) treatment. Neuroendocrine cells are cells that secrete regulatory peptides and biogenic amines in response to chemical, neural, or other types of stimuli. Neuroendocrine tumors (NET) arising from these cells can therefore secrete chemical mediators into the bloodstream to cause side effects in distant sites, a phenomenon called carcinoid syndrome. The most common peptides and amines secreted by NET are histamines, tachykinins, kallikrein, and serotonin. Overexposure to serotonin can cause severe diarrhea, one of the main clinical symptoms of carcinoid syndrome. Serotonin is metabolized in the urinary metabolite 5-hydroxy indole acetic acid (u5-HIAA), and high levels of u5-HIAA is associated with poor survival outcome in patients with NET. The first line treatment of carcinoid syndrome diarrhea is SSA, but symptoms still reoccur over the course of the disease. View MoreTelotristat Ethyl is the ethyl ester form of telotristat, 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. Xermelo is indicated for the treatment of carcinoid syndrome diarrhea in combination with somatostatin analog (SSA) therapy in adults inadequately controlled by SSA therapy. Xermelo is indicated for the treatment of carcinoid syndrome diarrhoea in combination with somatostatin analogue (SSA) therapy in adults inadequately controlled by SSA therapy. Absorption: After a single oral dose of telotristat ethyl to healthy subjects, telotristat ethyl was absorbed and metabolized to its active metabolite, telotristat. Peak plasma concentrations of telotristat ethyl were achieved within 0.5 to 2 hours, and those of telotristat within 1 to 3 hours. Plasma concentrations thereafter declined in a biphasic manner. Following administration of a single 500 mg dose of telotristat ethyl (twice the recommended dosage) under fasted conditions in healthy subjects, the mean Cmax and AUC0-inf were 4.4 ng/mL and 6.23 ng•hr/mL, respectively for telotristat ethyl. The mean Cmax and AUC0-inf were 610 ng/mL and 2320 ng•hr/mL, respectively for telotristat. Peak plasma concentrations and AUC of telotristat ethyl and telotristat appeared to be dose proportional following administration of a single dose of telotristat ethyl in the range of 100 mg (0.4 times the lowest recommended dose to 1000 mg [4 times the highest recommended dose]) under fasted conditions. Following multiple-dose administration of telotristat ethyl 500 mg three times daily, there was negligible accumulation at steady state for both telotristat ethyl and telotristat. In patients with metastatic neuroendocrine tumors and carcinoid syndrome diarrhea treated with SSA therapy, the median Tmax for telotristat ethyl and telotristat was approximately 1 and 2 hours, respectively. Following administration of 500 mg telotristat ethyl three times daily, with meals in patients, the mean Cmax and AUC0-6hr were approximately 7 ng/mL and 22 ng•hr/mL, respectively, for telotristat ethyl. The mean Cmax and AUC0-6hr were approximately 900 ng/mL and 3000 ng•hr/mL, respectively for telotristat. The pharmacokinetic parameters for both telotristat ethyl and telotristat were highly variable with about 55% coefficient of variation. Route of Elimination: Following a single 500 mg oral dose of 14C-telotristat ethyl, 93.2% of the dose was recovered over 240 hours: 92.8% was recovered in the feces, with less than 0.4% being recovered in the urine. Volume of Distribution: The estimated apparent total volume of distribution for the active metabolite from the Population PK model of 428.1 L in a typical healthy fasted subject and 348.7 L in patients with carcinoid syndrome. Clearance: The apparent total clearance at steady state (CL/Fss) following oral dosing with telotristat ethyl 500 mg three times daily for 14 days (twice the recommended dosage) in healthy subjects was 2.7 and 152 L/hr for telotristat ethyl and telotristat, respectively. Metabolism / Metabolites: After oral administration, telotristat ethyl undergoes hydrolysis via carboxylesterases to telotristat, its active metabolite. Telotristat is further metabolized. Among the metabolites of telotristat, the systemic exposure to an acid metabolite of oxidative deaminated decarboxylated telotristat was about 35% of that of telotristat. In vitro data suggest that telotristat ethyl and telotristat are not substrates for CYP enzymes. Biological Half-Life: Following a single 500 mg oral dose of telotristat ethyl in healthy subjects, the apparent half-life was approximately 0.6 hours for telotristat ethyl and 5 hours for telotristat. Mechanism of Action: Telotristat, the active metabolite of telotristat ethyl, is an inhibitor of tryptophan hydroxylase, which mediates the rate-limiting step in serotonin biosynthesis. The in vitro inhibitory potency of telotristat towards tryptophan hydroxylase is 29 times higher than that of telotristat ethyl. Serotonin plays a role in mediating secretion, motility, inflammation, and sensation of the gastrointestinal tract, and is over-produced in patients with carcinoid syndrome. Through inhibition of tryptophan hydroxylase, telotristat and telotristat ethyl reduce the production of peripheral serotonin, and the frequency of carcinoid syndrome diarrhea. |
Molecular Formula |
C27H26CLF3N6O3
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Molecular Weight |
C27H26ClF3N6O3
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Exact Mass |
574.17071
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Elemental Analysis |
C, 56.40; H, 4.56; Cl, 6.17; F, 9.91; N, 14.62; O, 8.35
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CAS # |
1033805-22-9
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Related CAS # |
Telotristat etiprate;1137608-69-5;Telotristat;1033805-28-5; 1033805-22-9 (ethyl); 1374745-52-4 (besilate)
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PubChem CID |
25181577
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Appearance |
Typically exists as Light yellow to yellow solids at room temperature
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Density |
1.4±0.1 g/cm3
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Boiling Point |
704.7±70.0 °C at 760 mmHg
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Flash Point |
380.0±35.7 °C
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Vapour Pressure |
0.0±2.2 mmHg at 25°C
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Index of Refraction |
1.621
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LogP |
5.47
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tPSA |
131.17
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InChi Key |
MDSQOJYHHZBZKA-GBXCKJPGSA-N
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InChi Code |
InChI=1S/C27H26ClF3N6O3/c1-3-39-25(38)20(32)12-16-4-6-17(7-5-16)21-14-23(35-26(33)34-21)40-24(27(29,30)31)19-9-8-18(28)13-22(19)37-11-10-15(2)36-37/h4-11,13-14,20,24H,3,12,32H2,1-2H3,(H2,33,34,35)/t20-,24+/m0/s1
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Chemical Name |
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
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Synonyms |
LX 1032; LX 1606; LX-1032; LX1606; LX1032; LX-1606; LX1606; LX 1606; Xermelo; Telotristat ethyl [USAN]; trade name: Xermelo
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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 |
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 (4.35 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 (4.35 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 corn oil and mix evenly.  (Please use freshly prepared in vivo formulations for optimal results.) |
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.