Identification

Name
Tasimelteon
Accession Number
DB09071  (DB05359)
Type
Small Molecule
Groups
Approved, Investigational
Description

Tasimelteon is a selective dual melatonin receptor agonist indicated for the treatment of Non-24-Hour Sleep-Wake Disorder (N24HSWD). Occurring commonly in blind individuals without light perception, this condition is often characterized by periods of night-time insomnia and day-time sleepiness. In blind individuals, a lack of light stimulation causes an extension of the 24-hour circadian cycle and can lead to progressively delayed sleep onset. By activating melatonin receptors MT1 and MT2 in the suprachiasmatic nucleus of the brain, tasimelteon has been shown to improve sleep by resynchronizing the circadian rhythm through its "non-photic" mechanism. Tasimelteon is currently the only drug available for the treatment of N24HSWD and was granted orphan drug status by the FDA in 2010.

Structure
Thumb
Synonyms
  • N-{[(1R,2R)-2-(2,3-dihydro-1-benzofuran-4-yl)cyclopropyl]methyl}propanamide
  • tasimeltéon
External IDs
BMS 214778 / BMS-214,778 / BMS-214778 / BMS214778 / VEC 162 / VEC-162 / VEC162
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
HetliozCapsule20 mgOralVanda Pharmaceuticals2015-07-03Not applicableEu
HetliozCapsule20 mg/1OralVanda Pharmaceuticals2014-04-04Not applicableUs
Categories
UNII
SHS4PU80D9
CAS number
609799-22-6
Weight
Average: 245.322
Monoisotopic: 245.141578856
Chemical Formula
C15H19NO2
InChI Key
PTOIAAWZLUQTIO-GXFFZTMASA-N
InChI
InChI=1S/C15H19NO2/c1-2-15(17)16-9-10-8-13(10)11-4-3-5-14-12(11)6-7-18-14/h3-5,10,13H,2,6-9H2,1H3,(H,16,17)/t10-,13+/m0/s1
IUPAC Name
N-{[(1R,2R)-2-(2,3-dihydro-1-benzofuran-4-yl)cyclopropyl]methyl}propanimidic acid
SMILES
[H][C@@]1(CN=C(O)CC)C[C@@]1([H])C1=C2CCOC2=CC=C1

Pharmacology

Indication

Tasimelteon is indicated for the treatment of Non-24-Hour Sleep-Wake Disorder (N24HSWD).

Associated Conditions
Pharmacodynamics
Not Available
Mechanism of action

Tasimelteon is a selective dual agonist of the melatonin receptors MT1 and MT2.

TargetActionsOrganism
AMelatonin receptor type 1A
agonist
Human
AMelatonin receptor type 1B
agonist
Human
Absorption
Not Available
Volume of distribution

The apparent oral volume of distribution of tasimelteon at steady state in young healthy subjects is approximately 56 - 126 L.

Protein binding

At therapeutic concentrations, tasimelteon is about 90% bound to proteins.

Metabolism

Tasimelteon is extensively metabolized. Metabolism of tasimelteon consists primarily of oxidation at multiple sites and oxidative dealkylation resulting in opening of the dihydrofuran ring followed by further oxidation to give a carboxylic acid. CYP1A2 and CYP3A4 are the major isozymes involved in the metabolism of tasimelteon. Phenolic glucuronidation is the major phase II metabolic route.

Route of elimination

Following oral administration of radiolabeled tasimelteon, 80% of total radioactivity was excreted in urine and approximately 4% in feces, resulting in a mean recovery of 84%. Less than 1% of the dose was excreted in urine as the parent compound.

Half life

The observed mean elimination half-life for tasimelteon is 1.3 ± 0.4 hours.

Clearance
Not Available
Toxicity

The most common adverse reactions are headache, increased alanine aminotransferase, nightmares or unusual dreams, and upper respiratory or urinary tract infections. There are currently no adequate or well-controlled studies that suggest that tasimelteon is safe to use during pregnancy. In animal studies, administration of tasimelteon during pregnancy resulted in developmental toxicity (embryofetal mortality, neurobehavioral impairment, and decreased growth and development in offspring) at doses greater than those used clinically. During clinical trials, rats did not self-administer tasimelteon, suggesting that the drug does not have a potential for abuse.

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of Tasimelteon can be decreased when combined with (R)-warfarin.
(S)-WarfarinThe metabolism of (S)-Warfarin can be decreased when combined with Tasimelteon.
2,5-Dimethoxy-4-ethylthioamphetamineThe risk or severity of adverse effects can be increased when Tasimelteon is combined with 2,5-Dimethoxy-4-ethylthioamphetamine.
3-isobutyl-1-methyl-7H-xanthineThe serum concentration of 3-isobutyl-1-methyl-7H-xanthine can be increased when it is combined with Tasimelteon.
3,4-MethylenedioxyamphetamineThe risk or severity of adverse effects can be increased when 3,4-Methylenedioxyamphetamine is combined with Tasimelteon.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Tasimelteon.
4-Bromo-2,5-dimethoxyamphetamineThe risk or severity of adverse effects can be increased when 4-Bromo-2,5-dimethoxyamphetamine is combined with Tasimelteon.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Tasimelteon.
4-MethoxyamphetamineThe risk or severity of adverse effects can be increased when 4-Methoxyamphetamine is combined with Tasimelteon.
5-androstenedioneThe metabolism of Tasimelteon can be decreased when combined with 5-androstenedione.
Food Interactions
Not Available

References

General References
  1. Lavedan C, Forsberg M, Gentile AJ: Tasimelteon: a selective and unique receptor binding profile. Neuropharmacology. 2015 Apr;91:142-7. doi: 10.1016/j.neuropharm.2014.12.004. Epub 2014 Dec 19. [PubMed:25534555]
  2. Neubauer DN: Tasimelteon for the treatment of non-24-hour sleep-wake disorder. Drugs Today (Barc). 2015 Jan;51(1):29-35. doi: 10.1358/dot.2015.51.1.2258364. [PubMed:25685859]
  3. Stahl SM: Mechanism of action of tasimelteon in non-24 sleep-wake syndrome: treatment for a circadian rhythm disorder in blind patients. CNS Spectr. 2014 Dec;19(6):475-8. doi: 10.1017/S1092852914000637. [PubMed:25422900]
  4. Vachharajani NN, Yeleswaram K, Boulton DW: Preclinical pharmacokinetics and metabolism of BMS-214778, a novel melatonin receptor agonist. J Pharm Sci. 2003 Apr;92(4):760-72. [PubMed:12661062]
External Links
KEGG Drug
D09388
PubChem Compound
10220503
PubChem Substance
310265003
ChemSpider
8395995
ChEBI
79042
ChEMBL
CHEMBL2103822
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Tasimelteon
ATC Codes
N05CH03 — Tasimelteon
FDA label
Download (249 KB)
MSDS
Download (203 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedBasic ScienceHealthy Volunteers4
1CompletedBasic ScienceHepatic Impairment1
1CompletedBasic ScienceImpaired Renal Function1
1CompletedBasic SciencePharmacodyamics and Pharmacokinetics of Tasimelteon Alone and in Combination With Ethanol1
1RecruitingTreatmentAutism Spectrum Conditions/Disorders / Circadian Rhythm Sleep Disorders / Non-24 Hour Sleep-Wake Disorder / Smith-Magenis Syndrome1
2CompletedTreatmentCircadian Rhythm Sleep Disorders1
2CompletedTreatmentJet Lag Disorder1
2, 3CompletedTreatmentMajor Depressive Disorder (MDD)1
2, 3RecruitingTreatmentCircadian / Smith-Magenis Syndrome1
3CompletedTreatmentJet Lag Type Insomnia1
3CompletedTreatmentNon-24-Hour Sleep-Wake Disorder3
3CompletedTreatmentPrimary Insomnia1
3CompletedTreatmentSleeplessness1
3RecruitingTreatmentNon 24 Hour Sleep Wake Disorder1
4CompletedBasic ScienceNon-24-Hour-Sleep-Wake Disorder1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
CapsuleOral20 mg
CapsuleOral20 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
USUS5856529 ANo1997-12-092017-12-09Us
USUS8785492 B2No2013-01-252033-01-25Us
US5856529No1997-12-092017-12-09Us
US8785492No2013-01-252033-01-25Us
US9060995No2013-01-252033-01-25Us
US9549913No2013-01-252033-01-25Us
US9539234No2013-01-252033-01-25Us
US9730910No2014-05-172034-05-17Us
USRE46604No2013-01-252033-01-25Us
US9855241No2013-01-252033-01-25Us
US10071977No2015-02-122035-02-12Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
boiling point (°C)442.553°CMSDS
water solubility1.1 mg/mLMSDS
logP2.43MSDS
Predicted Properties
PropertyValueSource
Water Solubility0.0216 mg/mLALOGPS
logP3.35ALOGPS
logP2.22ChemAxon
logS-4.1ALOGPS
pKa (Strongest Acidic)4.41ChemAxon
pKa (Strongest Basic)6.46ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area41.82 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity70.87 m3·mol-1ChemAxon
Polarizability27.91 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as coumarans. These are compounds containing the coumaran skeleton, which consists of a benzene ring fused to a 2,3-dihydrofuran ring.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Coumarans
Sub Class
Not Available
Direct Parent
Coumarans
Alternative Parents
Alkyl aryl ethers / Benzenoids / Secondary carboxylic acid amides / Oxacyclic compounds / Organopnictogen compounds / Organonitrogen compounds / Organic oxides / Hydrocarbon derivatives / Carbonyl compounds
Substituents
Coumaran / Alkyl aryl ether / Benzenoid / Carboxamide group / Secondary carboxylic acid amide / Oxacycle / Ether / Carboxylic acid derivative / Hydrocarbon derivative / Organic oxygen compound
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
monocarboxylic acid amide, 1-benzofurans, cyclopropanes (CHEBI:79042)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
General Function
Organic cyclic compound binding
Specific Function
High affinity receptor for melatonin. Likely to mediates the reproductive and circadian actions of melatonin. The activity of this receptor is mediated by pertussis toxin sensitive G proteins that ...
Gene Name
MTNR1A
Uniprot ID
P48039
Uniprot Name
Melatonin receptor type 1A
Molecular Weight
39374.315 Da
References
  1. Lavedan C, Forsberg M, Gentile AJ: Tasimelteon: a selective and unique receptor binding profile. Neuropharmacology. 2015 Apr;91:142-7. doi: 10.1016/j.neuropharm.2014.12.004. Epub 2014 Dec 19. [PubMed:25534555]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
General Function
Melatonin receptor activity
Specific Function
High affinity receptor for melatonin. Likely to mediates the reproductive and circadian actions of melatonin. The activity of this receptor is mediated by pertussis toxin sensitive G proteins that ...
Gene Name
MTNR1B
Uniprot ID
P49286
Uniprot Name
Melatonin receptor type 1B
Molecular Weight
40187.895 Da
References
  1. Lavedan C, Forsberg M, Gentile AJ: Tasimelteon: a selective and unique receptor binding profile. Neuropharmacology. 2015 Apr;91:142-7. doi: 10.1016/j.neuropharm.2014.12.004. Epub 2014 Dec 19. [PubMed:25534555]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Ogilvie BW, Torres R, Dressman MA, Kramer WG, Baroldi P: Clinical assessment of drug-drug interactions of tasimelteon, a novel dual melatonin receptor agonist. J Clin Pharmacol. 2015 Sep;55(9):1004-11. doi: 10.1002/jcph.507. Epub 2015 May 7. [PubMed:25851638]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
References
  1. Ogilvie BW, Torres R, Dressman MA, Kramer WG, Baroldi P: Clinical assessment of drug-drug interactions of tasimelteon, a novel dual melatonin receptor agonist. J Clin Pharmacol. 2015 Sep;55(9):1004-11. doi: 10.1002/jcph.507. Epub 2015 May 7. [PubMed:25851638]
  2. Tasimelteon FDA label [File]

Drug created on May 14, 2015 10:07 / Updated on November 02, 2018 06:58