Identification

Name
Lemborexant
Accession Number
DB11951
Type
Small Molecule
Groups
Approved, Investigational
Description

Lemborexant is a novel dual orexin receptor antagonist used in the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance.5 Recent research in the field of sleep disorders has revealed that insomnia is likely driven not by the inability of the brain to "switch on" sleep-related circuits, but rather an inability to "switch-off" wake-promoting circuits.3,4 Whereas historically popular pharmacologic treatments for insomnia (e.g. zopiclone, zolpidem, benzodiazepines) focus on enhancing sleep drive via modulation of GABA and melatonin receptors, lemborexant and other orexin antagonists (e.g. suvorexant) act to counteract inappropriate wakefulness.3 This novel mechanism of action offers potential advantages over classic hypnotic agents, including a more favorable adverse effect profile and potentially greater efficacy, and may signal the beginning of a new wave of treatment options for patients suffering from insomnia.3

Structure
Thumb
Synonyms
  • Lemborexant
External IDs
E 2006 / E-2006 / E2006
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
DayvigoTablet, film coated5 mg/1OralEisai Inc.2020-04-07Not applicableUs
DayvigoTablet, film coated10 mg/1OralEisai Inc.2020-04-07Not applicableUs
DayvigoTablet, film coated5 mg/1OralEisai Inc.2020-04-07Not applicableUs
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories
UNII
0K5743G68X
CAS number
1369764-02-2
Weight
Average: 410.425
Monoisotopic: 410.155432226
Chemical Formula
C22H20F2N4O2
InChI Key
MUGXRYIUWFITCP-PGRDOPGGSA-N
InChI
InChI=1S/C22H20F2N4O2/c1-13-19(11-25-14(2)27-13)30-12-22(15-4-3-5-16(23)8-15)9-18(22)21(29)28-20-7-6-17(24)10-26-20/h3-8,10-11,18H,9,12H2,1-2H3,(H,26,28,29)/t18-,22+/m0/s1
IUPAC Name
(1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropane-1-carboxamide
SMILES
CC1=NC=C(OC[C@]2(C[C@H]2C(=O)NC2=NC=C(F)C=C2)C2=CC=CC(F)=C2)C(C)=N1

Pharmacology

Indication

Lemborexant is indicated for the treatment of adult patients with insomnia characterized by difficulties with sleep onset and/or sleep maintenance.5

Associated Conditions
Pharmacodynamics

Lemborexant promotes sleep by antagonizing the actions of wake-promoting chemicals in the brain.5 Episodes of complex sleep behaviors (e.g. eating food, having sex, making phone calls) have been reported in patients using lemborexant - these events may occur in hypnotic-naive and hyponotic-experienced patients, and patients are unlikely to remember these events. Patients exhibiting complex sleep behaviors should discontinue lemborexant immediately. Lemborexant may carry some risk of abuse, and should be used with caution in patients with a history of alcohol or drug addiction. Its controlled substance schedule is currently under review by the Drug Enforcement Administration.5

Mechanism of action

The orexin neuropeptide signaling system is involved in many physiologic functions, including sleep/wake control. Orexin-A and orexin-B activate post-synaptic G-protein coupled2 orexin-1 receptors (OX1R) and orexin-2 receptors (OX2R), which are found on neurons in the hypothalamus that project to numerous wake-controlling nuclei. Each receptor carries slightly different activity - activation of OX1R appears to suppress the onset of rapid eye movement (REM) sleep, whereas activation of OX2R appears to suppress non-REM sleep.3

Lemborexant is an competitive antagonist of OX1R and OX2R. By blocking the binding of wake-promoting orexin-A and -B at these receptors, lemborexant suppresses the wake-drive, thereby promoting sleep.5

TargetActionsOrganism
AOrexin receptor type 1
antagonist
Humans
AOrexin receptor type 2
antagonist
Humans
Additional Data Available
Adverse Effects

Comprehensive structured data on known drug adverse effects with statistical prevalence. MedDRA and ICD10 ids are provided for adverse effect conditions and symptoms.

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Additional Data Available
Contraindications

Structured data covering drug contraindications. Each contraindication describes a scenario in which the drug is not to be used. Includes restrictions on co-administration, contraindicated populations, and more.

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Additional Data Available
Blackbox Warnings

Structured data representing warnings from the black box section of drug labels. These warnings cover important and dangerous risks, contraindications, or adverse effects.

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Absorption

Animal models of lemborexant disposition have demonstrated rapid absorption following oral administration.2 The Tmax of lemborexant is approximately 1-3 hours, or 3-5 hours following administration of a high-fat, high-calorie meal.5 Cmax and AUC0-24h increase at a rate slightly less than proportionate to the given dose. Following administration of a high-fat, high-calorie meal, Cmax is decreased by 23% and AUC0-inf is increased by 18%.5 AUC, Cmax, and terminal half-life are increased in the presence of moderate hepatic impairment, and AUC (but not half-life) is increased in the presence of mild hepatic impairment.5

Volume of distribution

The volume of distribution of lemborexant is 1970 L, indicating extensive tissue distribution.5

Protein binding

Lemborexant is approximately 94% protein-bound in vitro, though the specific proteins to which it binds in plasma have not been elucidated.5

Metabolism

Given that less than 1% of an administered dose is recovered unchanged in the urine,5 it is likely that lemborexant is extensively metabolized - this has been confirmed in rat and monkey models,2 but its metabolism in humans has not been fully characterized. Prescribing information states that it is predominantly metabolized by CYP3A4, with a smaller contribution by CYP3A5. The major circulating metabolite is lemborexant's M10 metabolite, which is pharmacologically active and binds to orexin receptors with a similar affinity to the parent drug. The M10 metabolite has the potential to induce CYP3A and CYP2B6 enzymes, weakly inhibit CYP3A enzymes, and is a substrate of P-gp transporters.5

Route of elimination

Following oral administration, 57.4% of the dose is found in the feces and 29.1% in the urine. Less than 1% of the dose recovered in the urine exists as unchanged parent drug, suggesting extensive metabolism.5

Half life

The half-life for lemborexant at doses of 5mg and 10mg is 17 and 19 hours, respectively.5

Clearance
Not Available
Toxicity

Clinical experience with lemborexant overdose is limited. In clinical studies, healthy patients receiving doses up to 10x the recommended maximum dose experienced dose-dependent increases in the frequency of adverse effects such as somnolence - it is likely, then, that symptoms of overdose will be consistent with lemborexant's adverse effect profile.5 In the event of an overdosage, implement supportive measures and consult the nearest poison control center for the most up to date management strategies. As lemborexant is highly protein-bound, hemodialysis is likely to be of little use in overdose situations.5

Affected organisms
  • Humans and other mammals
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.
DrugInteraction
2,5-Dimethoxy-4-ethylthioamphetamineThe risk or severity of adverse effects can be increased when Lemborexant is combined with 2,5-Dimethoxy-4-ethylthioamphetamine.
4-Bromo-2,5-dimethoxyamphetamineThe risk or severity of adverse effects can be increased when 4-Bromo-2,5-dimethoxyamphetamine is combined with Lemborexant.
4-MethoxyamphetamineThe risk or severity of adverse effects can be increased when 4-Methoxyamphetamine is combined with Lemborexant.
5-methoxy-N,N-dimethyltryptamineThe risk or severity of adverse effects can be increased when Lemborexant is combined with 5-methoxy-N,N-dimethyltryptamine.
7-NitroindazoleThe risk or severity of adverse effects can be increased when 7-Nitroindazole is combined with Lemborexant.
7,8-Dichloro-1,2,3,4-tetrahydroisoquinolineThe risk or severity of adverse effects can be increased when 7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline is combined with Lemborexant.
AbataceptThe metabolism of Lemborexant can be increased when combined with Abatacept.
AcalabrutinibThe serum concentration of Lemborexant can be increased when it is combined with Acalabrutinib.
AcepromazineThe risk or severity of adverse effects can be increased when Acepromazine is combined with Lemborexant.
AceprometazineThe risk or severity of adverse effects can be increased when Aceprometazine is combined with Lemborexant.
Additional Data Available
  • Extended Description
    Extended Description

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  • Severity
    Severity

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Food Interactions
  • Take on an empty stomach. Co-administration with food delays absorption and sleep onset.

References

Synthesis Reference

Yoshida, Y. et. al. "Discovery of (1R,2S)-2-{[(2,4-Dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide (E2006): A Potent and Efficacious Oral Orexin Receptor Antagonist," J. Med. Chem. 2015, 58, 11, 4648-4664.

General References
  1. Mahoney CE, Mochizuki T, Scammell TE: Dual orexin receptor antagonists increase sleep and cataplexy in wild type mice. Sleep. 2019 Dec 13. pii: 5674930. doi: 10.1093/sleep/zsz302. [PubMed:31830270]
  2. Ueno T, Ishida T, Kusano K: Disposition and metabolism of [(14)C]lemborexant, a novel dual orexin receptor antagonist, in rats and monkeys. Xenobiotica. 2019 Jun;49(6):688-697. doi: 10.1080/00498254.2018.1482509. Epub 2018 Jul 5. [PubMed:29806508]
  3. Beuckmann CT, Suzuki M, Ueno T, Nagaoka K, Arai T, Higashiyama H: In Vitro and In Silico Characterization of Lemborexant (E2006), a Novel Dual Orexin Receptor Antagonist. J Pharmacol Exp Ther. 2017 Aug;362(2):287-295. doi: 10.1124/jpet.117.241422. Epub 2017 May 30. [PubMed:28559480]
  4. Beuckmann CT, Ueno T, Nakagawa M, Suzuki M, Akasofu S: Preclinical in vivo characterization of lemborexant (E2006), a novel dual orexin receptor antagonist for sleep/wake regulation. Sleep. 2019 Jun 11;42(6). pii: 5421821. doi: 10.1093/sleep/zsz076. [PubMed:30923834]
  5. FDA Approved Drug Products: Dayvigo (lemborexant) oral tablets [Link]
  6. Carbosynth: Lemborexant MSDS [Link]
External Links
PubChem Compound
56944144
PubChem Substance
347828277
ChemSpider
34500836
BindingDB
50093793
RxNav
2272403
ChEMBL
CHEMBL3545367
ZINC
ZINC000118073503
PDBe Ligand
NRK
Wikipedia
Lemborexant
PDB Entries
6tot
FDA label
Download (586 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedBasic ScienceHealthy Volunteers3
1CompletedOtherHealthy Volunteers / OSAS (Obstructive Sleep Apneas Syndrome)1
1CompletedTreatmentCNS1
1CompletedTreatmentHealthy Volunteers3
1CompletedTreatmentHepatic Impairment1
1CompletedTreatmentInsomnia2
1CompletedTreatmentInsomnia Disorder1
1CompletedTreatmentInsomnia Disorders1
1CompletedTreatmentMetabolism and Excretion1
1CompletedTreatmentImpaired kidney function1
2Active Not RecruitingTreatmentIrregular Sleep-Wake Rhythm Disorder1
2CompletedTreatmentAdults / Elderly / Insomnia Chronic1
3Active Not RecruitingTreatmentInsomnia1
3CompletedTreatmentInsomnia1
3CompletedTreatmentInsomnia Disorder1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Tablet, film coatedOral10 mg/1
Tablet, film coatedOral5 mg/1
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0111 mg/mLALOGPS
logP3.39ALOGPS
logP3.34ChemAxon
logS-4.6ALOGPS
pKa (Strongest Acidic)12.12ChemAxon
pKa (Strongest Basic)3.15ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area77 Å2ChemAxon
Rotatable Bond Count6ChemAxon
Refractivity107.94 m3·mol-1ChemAxon
Polarizability40.54 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
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 n-arylamides. These are organic compounds that contain a carboxamide group that is N-linked to a aryl group. They have the generic structure RC(=O)N(R')H, R = organyl group and R'= aryl group.
Kingdom
Organic compounds
Super Class
Organic nitrogen compounds
Class
Organonitrogen compounds
Sub Class
N-arylamides
Direct Parent
N-arylamides
Alternative Parents
Fluorobenzenes / Alkyl aryl ethers / Pyrimidines and pyrimidine derivatives / Pyridines and derivatives / Imidolactams / Cyclopropanecarboxylic acids and derivatives / Aryl fluorides / Heteroaromatic compounds / Secondary carboxylic acid amides / Azacyclic compounds
show 4 more
Substituents
N-arylamide / Alkyl aryl ether / Fluorobenzene / Halobenzene / Aryl fluoride / Aryl halide / Monocyclic benzene moiety / Cyclopropanecarboxylic acid or derivatives / Imidolactam / Benzenoid
show 17 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
Peptide hormone binding
Specific Function
Moderately selective excitatory receptor for orexin-A and, with a lower affinity, for orexin-B neuropeptide. Seems to be exclusively coupled to the G(q) subclass of heteromeric G proteins, which ac...
Gene Name
HCRTR1
Uniprot ID
O43613
Uniprot Name
Orexin receptor type 1
Molecular Weight
47535.33 Da
References
  1. FDA Approved Drug Products: Dayvigo (lemborexant) oral tablets [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
Peptide hormone binding
Specific Function
Nonselective, high-affinity receptor for both orexin-A and orexin-B neuropeptides.
Gene Name
HCRTR2
Uniprot ID
O43614
Uniprot Name
Orexin receptor type 2
Molecular Weight
50693.965 Da

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
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. FDA Approved Drug Products: Dayvigo (lemborexant) oral tablets [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Oxygen binding
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
CYP3A5
Uniprot ID
P20815
Uniprot Name
Cytochrome P450 3A5
Molecular Weight
57108.065 Da
References
  1. FDA Approved Drug Products: Dayvigo (lemborexant) oral tablets [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inducer
General Function
Steroid 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 oxidizes a variety of structurally un...
Gene Name
CYP2B6
Uniprot ID
P20813
Uniprot Name
Cytochrome P450 2B6
Molecular Weight
56277.81 Da
References
  1. FDA Approved Drug Products: Dayvigo (lemborexant) oral tablets [Link]
Kind
Protein group
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
Inducer
Curator comments
From Dayvigo prescribing information: "...lemborexant and M10 have the potential to induce CYP3A and the weak potential to inhibit CYP3A...". The extent of each is unclear.
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...

Components:
References
  1. FDA Approved Drug Products: Dayvigo (lemborexant) oral tablets [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. FDA Approved Drug Products: Dayvigo (lemborexant) oral tablets [Link]

Drug created on October 20, 2016 15:04 / Updated on March 19, 2020 14:24

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