Basic information
- CAS
1033805-22-9- Standard SMILES
CCOC(=O)[C@@H](N)Cc1ccc(-c2cc(O[C@H](c3ccc(Cl)cc3-n3ccc(C)n3)C(F)(F)F)nc(N)n2)cc1- InChIKey
MDSQOJYHHZBZKA-GBXCKJPGSA-N- Molecular formula
- C27H26ClF3N6O3
- Average molar mass
- 575 g/mol
- Monoisotopic mass
- 574.17070103
Overview
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.
Names & identifiers
- Preferred name
- Telotristat Ethyl
- IUPAC
- 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
- English name
- LX-1606 Hippurate
- Molecular formula
- C27H26ClF3N6O3
- Molecular weight
- 574.98
Names & synonyms
TELOTRISTAT ETHYL1033805-22-9LX1606LX-1606LX 1606LX1032LX 1032LX-1032DTXSID001102271ethyl (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]propanoate8G388563M7ethyl (2S)-2-amino-3-(4-{2-amino-6-[(1R)-1-[4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl]-2,2,2-trifluoroethoxy]pyrimidin-4-yl}phenyl)propanoate
Show more names
TelotristaLX-1606 HippurateEthyl TelotristatLX 1606 (Telotristat)2H7]-Telotristat ethylTELOTRISTAT ETHYL (LX1606)LX1606 (Telotristat ethyl)
ethyl (2S)-2-amino-3-(4-(2-amino-6-((1R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoateethyl (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)propanoateRefChem:57926DTXCID9015339564-(2-Amino-6-((1R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-4-pyrimidinyl)-L-phenylalanine ethyl esterXermeloTelotristat ethyl [USAN](S)-Ethyl 2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate
Properties
Computed structural properties
- XLogP
- 5.1
- Topological polar surface area
- 131 Ų
- Hydrogen bond donors
- 2
- Hydrogen bond acceptors
- 11
- Rotatable bonds
- 10
- Heavy atoms
- 40
- Formal charge
- 0
- Complexity
- 821
Experimental & physicochemical properties
Drugs
Pharmaceuticals -> Listed in ZINC15
Pharmaceuticals -> Alimentary tract and metabolism -> Other alimentary tract and metabolism products
Human DrugsEMA approved medicines: Human medicine (Orphan designations)
Physicochemical properties
- Melting point
- 80 · 80-82°C
- Boiling point
- 704.7 · 704.7±70.0 °C(Predicted)
- Density
- 1.42 · 1.42
- storage temp.
- -20 °C · -20°C Freezer, Under inert atmosphere
- solubility
- DMSO (Slightly), Methanol (Slightly)
- pka
- 6.72 · 6.72±0.33(Predicted)
- form
- Solid
- color
- White to Off-White
- InChIKey
- MDSQOJYHHZBZKA-GBXCKJPGSA-N
- SMILES
- C(OCC)(=O)[C@H](CC1=CC=C(C2C=C(O[C@H](C3=CC=C(Cl)C=C3N3C=CC(C)=N3)C(F)(F)F)N=C(N)N=2)C=C1)N
Safety & regulation
GHS classification
GHS ClassificationNot Classified
Hazard information
Hazard Classes and CategoriesNot Classified
Safety data
- Signal word
- Warning
- Symbol(GHS)
- GHS07
- Hazard statements
- H302-H315-H319-H335
- Precautionary statements
- P261-P305+P351+P338
Chemistry & industry
Pharmacology
Protein BindingBoth telotristat ethyl and telotristat are greater than 99% bound to human plasma proteins.
Pharmacodynamics
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 gastrointestinal 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. Gastrointestinal motility studies were conducted in rats using the charcoal meal test. There was a significant dose-related delay in both gastrointestinal transit and gastric emptying, associated with a reduction in blood serotonin levels and proximal colon serotonin. A quantitative whole-body autoradiography study was conducted to assess the absorption, distribution and excretion of radioactivity in rats following a single oral dose of telotristat etiprate labeled with carbon 14. Rats were administered either 30 mg/kg or 100 mg/kg of the compound. The distribution of radioactivity was limited to tissues of the hepatic and renal system and the contents of the GI tract. There was no measurable radioactivity in the brain at any dose tested.
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.
Biological Half-LifeFollowing 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.
Metabolism/Metabolites
Related reactions
2 records
Compound notes
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