Identification
- Summary
Telotristat ethyl is a tryptophan hydroxylase inhibitor used to treat carcinoid syndrome.
- Brand Names
- Xermelo
- Generic Name
- Telotristat ethyl
- DrugBank Accession Number
- DB12095
- Background
Telotristat only approved oral therapy for carcinoid syndrome diarrhea. Telotristat was approved by the FDA in March, 2017 as Xermelo.
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Telotristat ethyl (DB12095)
- Weight
- Average: 574.99
Monoisotopic: 574.1707009 - Chemical Formula
- C27H26ClF3N6O3
- Synonyms
- Telotristat ethyl
- External IDs
- LX 1032
- LX 1606
- LX-1032
- LX-1606
- LX1032
- LX1606
Pharmacology
- Indication
As a serotonin synthesis inhibitor, telotristat etiprate, has the potential to reduce serotonin levels and address the key elements of carcinoid syndrome.
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- Contraindications & Blackbox Warnings
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Activity is mainly in the gastrointestinal tract, with minimal effects reported on the brain and cardiovascular system, accompanied by an excellent safety profile. 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 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. While existing treatments for carcinoid syndrome work to reduce the release of serotonin outside tumor cells, telotristat etiprate works at the source to reduce serotonin production within the tumor cells. By specifically inhibiting serotonin production, telotristat etiprate seeks to control this important driver of carcinoid syndrome and, in turn, provide patients with more control over their disease.
Target Actions Organism ATryptophan 5-hydroxylase 2 antagonistHumans ATryptophan 5-hydroxylase 1 antagonistHumans - Absorption
Low systemic absorption. Tmax of 2–4 h, supporting the 8-hourly administration
- Volume of distribution
Not Available
- Protein binding
High plasma protein binding of its active metabolite, Telotristat.
- Metabolism
Metabolized by the liver.
- Route of elimination
Telotristat ethyl is mainly excreted in feces.
- Half-life
4–12 h
- Clearance
Not available
- Adverse Effects
Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates.Improve decision support & research outcomes with our structured adverse effects data.- Toxicity
Telotristat causes depression and constipation in high doses.
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.Not Available
- Food Interactions
- Take with food. Food increases the bioavailability of telotristat ethyl.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Product Ingredients
Ingredient UNII CAS InChI Key Telotristat etiprate 3T25U84H4U 1137608-69-5 XSFPZBUIBYMVEA-CELUQASASA-N - Active Moieties
Name Kind UNII CAS InChI Key Telotristat prodrug 381V4FCV2Z 1033805-28-5 NCLGDOBQAWBXRA-PGRDOPGGSA-N - Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Xermelo Tablet 250 mg/1 Oral Lexicon Pharmaceuticals, Inc. 2017-03-01 Not applicable US 
Xermelo Tablet 250 mg Oral Ipsen Biopharmaceuticals Canada Inc 2018-12-07 Not applicable Canada 
Xermelo Tablet, film coated 250 mg Oral Ipsen Pharma 2020-12-16 Not applicable EU 
Xermelo Tablet 250 mg/1 Oral Tersera Therapeutics Llc 2020-10-05 Not applicable US Xermelo Tablet, film coated 250 mg Oral Ipsen Pharma 2020-12-16 Not applicable EU
Categories
- Drug Categories
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as phenylalanine and derivatives. These are compounds containing phenylalanine or a derivative thereof resulting from reaction of phenylalanine at the amino group or the carboxy group, or from the replacement of any hydrogen of glycine by a heteroatom.
- Kingdom
- Organic compounds
- Super Class
- Organic acids and derivatives
- Class
- Carboxylic acids and derivatives
- Sub Class
- Amino acids, peptides, and analogues
- Direct Parent
- Phenylalanine and derivatives
- Alternative Parents
- Alpha amino acid esters / Phenylpyrimidines / Phenylpyrazoles / Amphetamines and derivatives / Alkyl aryl ethers / Aminopyrimidines and derivatives / Aralkylamines / Chlorobenzenes / Fatty acid esters / Aryl chlorides show 11 more
- Substituents
- 4-phenylpyrimidine / Alkyl aryl ether / Alkyl fluoride / Alkyl halide / Alpha-amino acid ester / Amine / Aminopyrimidine / Amphetamine or derivatives / Aralkylamine / Aromatic heteromonocyclic compound show 31 more
- Molecular Framework
- Aromatic heteromonocyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- 8G388563M7
- CAS number
- 1033805-22-9
- InChI Key
- MDSQOJYHHZBZKA-GBXCKJPGSA-N
- InChI
- 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
- IUPAC Name
- 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)propanoate
- SMILES
- CCOC(=O)[C@@H](N)CC1=CC=C(C=C1)C1=NC(N)=NC(O[C@H](C2=CC=C(Cl)C=C2N2C=CC(C)=N2)C(F)(F)F)=C1
References
- General References
- Lamarca A, Barriuso J, McNamara MG, Hubner RA, Valle JW: Telotristat ethyl: a new option for the management of carcinoid syndrome. Expert Opin Pharmacother. 2016 Dec;17(18):2487-2498. Epub 2016 Nov 16. [Article]
- Kulke MH, O'Dorisio T, Phan A, Bergsland E, Law L, Banks P, Freiman J, Frazier K, Jackson J, Yao JC, Kvols L, Lapuerta P, Zambrowicz B, Fleming D, Sands A: Telotristat etiprate, a novel serotonin synthesis inhibitor, in patients with carcinoid syndrome and diarrhea not adequately controlled by octreotide. Endocr Relat Cancer. 2014 Oct;21(5):705-14. doi: 10.1530/ERC-14-0173. Epub 2014 Jul 10. [Article]
- FDA Review- Telotristat [Link]
- External Links
- PubChem Compound
- 25025298
- PubChem Substance
- 347828399
- ChemSpider
- 28189674
- 1872441
- ChEMBL
- CHEMBL2105695
- ZINC
- ZINC000043205655
- Wikipedia
- Telotristat_ethyl
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 3 Completed Treatment Carcinoid Syndrome 3 3 Recruiting Treatment Locally Advanced Well Differentiated Neuroendocrine Neoplasm / Metastatic Well Differentiated Neuroendocrine Neoplasm 1 3 Withdrawn Treatment Carcinoid Heart Disease / Small Intestinal NET 1 2 Completed Treatment Carcinoid Syndrome 2 2 Completed Treatment Ulcerative Colitis 1 2 Recruiting Supportive Care Locally Advanced Unresectable Pancreatic Adenocarcinoma / Pancreatic Adenocarcinoma Metastatic / Recurrent Pancreatic Adenocarcinoma / Stage III Pancreatic Cancer AJCC v8 / Stage IV Pancreatic Cancer AJCC v8 1 2 Recruiting Treatment Carcinoid Syndrome / Metastatic Nonfunctional Well Differentiated Neuroendocrine Neoplasm 1 2 Recruiting Treatment Neuroendocrine Tumors 1 2 Terminated Treatment Biliary Tract Cancer (BTC) 1 2 Withdrawn Supportive Care Carcinoid Syndrome / Diarrhea / Neuroendocrine Tumors 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet Oral 250 mg Tablet Oral 250 mg/1 Tablet, film coated Oral 250 MG - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US7553840 No 2009-06-30 2027-12-11 US US8193204 No 2012-06-05 2031-02-27 US US7968559 No 2011-06-28 2027-12-11 US US8653094 No 2014-02-18 2028-12-19 US US7709493 No 2010-05-04 2027-12-11 US
Properties
- State
- Solid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.00294 mg/mL ALOGPS logP 5.35 ALOGPS logP 5.54 ChemAxon logS -5.3 ALOGPS pKa (Strongest Acidic) 16.06 ChemAxon pKa (Strongest Basic) 6.94 ChemAxon Physiological Charge 1 ChemAxon Hydrogen Acceptor Count 7 ChemAxon Hydrogen Donor Count 2 ChemAxon Polar Surface Area 131.17 Å2 ChemAxon Rotatable Bond Count 11 ChemAxon Refractivity 144.98 m3·mol-1 ChemAxon Polarizability 55.38 Å3 ChemAxon Number of Rings 4 ChemAxon Bioavailability 0 ChemAxon Rule of Five No ChemAxon Ghose Filter No ChemAxon Veber's Rule No ChemAxon MDDR-like Rule Yes ChemAxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Not Available
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Antagonist
- General Function
- Tryptophan 5-monooxygenase activity
- Specific Function
- Not Available
- Gene Name
- TPH2
- Uniprot ID
- Q8IWU9
- Uniprot Name
- Tryptophan 5-hydroxylase 2
- Molecular Weight
- 56056.295 Da
References
- Kulke MH, O'Dorisio T, Phan A, Bergsland E, Law L, Banks P, Freiman J, Frazier K, Jackson J, Yao JC, Kvols L, Lapuerta P, Zambrowicz B, Fleming D, Sands A: Telotristat etiprate, a novel serotonin synthesis inhibitor, in patients with carcinoid syndrome and diarrhea not adequately controlled by octreotide. Endocr Relat Cancer. 2014 Oct;21(5):705-14. doi: 10.1530/ERC-14-0173. Epub 2014 Jul 10. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Antagonist
- General Function
- Tryptophan 5-monooxygenase activity
- Specific Function
- Not Available
- Gene Name
- TPH1
- Uniprot ID
- P17752
- Uniprot Name
- Tryptophan 5-hydroxylase 1
- Molecular Weight
- 50984.725 Da
References
- Kulke MH, O'Dorisio T, Phan A, Bergsland E, Law L, Banks P, Freiman J, Frazier K, Jackson J, Yao JC, Kvols L, Lapuerta P, Zambrowicz B, Fleming D, Sands A: Telotristat etiprate, a novel serotonin synthesis inhibitor, in patients with carcinoid syndrome and diarrhea not adequately controlled by octreotide. Endocr Relat Cancer. 2014 Oct;21(5):705-14. doi: 10.1530/ERC-14-0173. Epub 2014 Jul 10. [Article]
Drug created at October 20, 2016 21:20 / Updated at May 24, 2022 11:53