Telotristat ethyl

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
Thumb
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.

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

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.

TargetActionsOrganism
ATryptophan 5-hydroxylase 2
antagonist
Humans
ATryptophan 5-hydroxylase 1
antagonist
Humans
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
Medicalerrors
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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

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Product Ingredients
IngredientUNIICASInChI Key
Telotristat etiprate3T25U84H4U1137608-69-5XSFPZBUIBYMVEA-CELUQASASA-N
Active Moieties
NameKindUNIICASInChI Key
Telotristatprodrug381V4FCV2Z1033805-28-5NCLGDOBQAWBXRA-PGRDOPGGSA-N
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
XermeloTablet, film coated250 mgOralIpsen Pharma2020-12-16Not applicableEU flag
XermeloTablet250 mg/1OralLexicon Pharmaceuticals, Inc.2017-03-01Not applicableUS flag
XermeloTablet250 mgOralIpsen Biopharmaceuticals Canada Inc2018-12-07Not applicableCanada flag
XermeloTablet, film coated250 mgOralIpsen Pharma2020-12-16Not applicableEU flag
XermeloTablet250 mg/1OralTersera Therapeutics Llc2020-10-05Not applicableUS flag

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
  1. 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]
  2. 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]
  3. FDA Review- Telotristat [Link]
PubChem Compound
25025298
PubChem Substance
347828399
ChemSpider
28189674
RxNav
1872441
ChEMBL
CHEMBL2105695
ZINC
ZINC000043205655
Wikipedia
Telotristat_ethyl
AHFS Codes
  • 56:08.00 — Antidiarrhea Agents

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedTreatmentCarcinoid Syndrome3
3Not Yet RecruitingTreatmentLocally Advanced Well Differentiated Neuroendocrine Neoplasm / Metastatic Well Differentiated Neuroendocrine Neoplasm1
3WithdrawnTreatmentCarcinoid Heart Disease / Small Intestinal NET1
2Active Not RecruitingTreatmentBiliary Tract Cancer1
2CompletedTreatmentCarcinoid Syndrome2
2CompletedTreatmentUlcerative Colitis1
2Not Yet RecruitingTreatmentAdvanced Neuroendocrine Neoplasm / Carcinoid Syndrome1
2Not Yet RecruitingTreatmentNeuroendocrine Tumors2
2RecruitingSupportive CareCarcinoid Syndrome / Diarrhoea / Neuroendocrine Tumors1
2RecruitingSupportive CareLocally Advanced Unresectable Pancreatic Adenocarcinoma / Pancreatic Adenocarcinoma Metastatic / Recurrent Pancreatic Adenocarcinoma / Stage III Pancreatic Cancer AJCC v8 / Stage IV Pancreatic Cancer AJCC v81

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
TabletOral250 mg/1
TabletOral250 mg
Tablet, film coatedOral
Tablet, film coatedOral250 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US7553840No2009-06-302027-12-11US flag
US8193204No2012-06-052031-02-27US flag
US7968559No2011-06-282027-12-11US flag
US8653094No2014-02-182028-12-19US flag
US7709493No2010-05-042027-12-11US flag

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00294 mg/mLALOGPS
logP5.35ALOGPS
logP5.54ChemAxon
logS-5.3ALOGPS
pKa (Strongest Acidic)16.06ChemAxon
pKa (Strongest Basic)6.94ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count7ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area131.17 Å2ChemAxon
Rotatable Bond Count11ChemAxon
Refractivity144.98 m3·mol-1ChemAxon
Polarizability55.38 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Targets

Drugtargets
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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
  1. 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
  1. 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 on October 20, 2016 21:20 / Updated on June 18, 2021 14:15