Suvorexant

Identification

Summary

Suvorexant is a orexin receptor antagonist used to treat insomnia that is characterized by difficulties with sleep onset and/or sleep maintenance.

Brand Names
Belsomra
Generic Name
Suvorexant
DrugBank Accession Number
DB09034
Background

Suvorexant is a selective dual antagonist of orexin receptors OX1R and OX2R that promotes sleep by reducing wakefulness and arousal. It has been approved for the treatment of insomnia.

Type
Small Molecule
Groups
Approved, Investigational
Structure
Weight
Average: 450.93
Monoisotopic: 450.1571017
Chemical Formula
C23H23ClN6O2
Synonyms
  • Suvorexant
External IDs
  • MK 4305
  • MK-4305
  • MK4305

Pharmacology

Indication

Suvorexant is indicated for the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance.

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofInsomnia••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Not Available

Mechanism of action

Suvorexant is a dual antagonist of orexin receptors OX1R and OX2R. It exerts its pharmacological effect by inhibiting binding of neuropeptides orexin A and B, also known as hypocretin 1 and 2, that are produced by neurons in the lateral hypothalamus. These neurons control the wake-promoting centers of the brain and are active during wakefulness, especially during motor activities, and stop firing during sleep. By inhibiting the reinforcement of arousal systems, suvorexant use causes a decrease in arousal and wakefulness, rather than having a direct sleep-promoting effect.

TargetActionsOrganism
AOrexin receptor type 1
antagonist
Humans
AOrexin receptor type 2
antagonist
Humans
Absorption

Peak concentrations occur at a median Tmax of 2 hours under fasted conditions. Ingestion of suvorexant with a high-fat meal has no effect on AUC or Cmax, but may delay Tmax by approximately 1.5 hours. Mean absolute bioavailability of 10 mg is 82%.

Volume of distribution

Mean volume of distribution is approximately 49 litres.

Protein binding

Suvorexant is extensively bound (>99%) to human plasma proteins and does not preferentially distribute into red blood cells. It binds to both human serum albumin and alpha1-acid glycoprotein.

Metabolism

Suvorexant is primarily metabolized by cytochrome-P450 3A4 enzyme (CYP3A4) with a minor contribution from CYP2C19. Major circulating metabolites are suvorexant and a hydroxy-suvorexant metabolite, which is not expected to be pharmacologically active. There is potential for drug-drug interactions with drugs that inhibit or induce CYP3A4 activity.

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Route of elimination

Approximately 66% is eliminated in feces and 23% is eliminated in urine.

Half-life

Mean half life is approximately 12 hours.

Clearance

Not Available

Adverse Effects
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Toxicity

Dose-related somnolence and CNS depression are the most common adverse effects associated with the use of suvorexant. It has also been shown to impair driving skills and may increase the risk of falling asleep while driving. Next-day impairments are found to be highest if suvorexant is taken with less than a full night of sleep remaining, with higher doses, or if co-administered with other CNS depressants or CYP3A inhibitors. Complex behaviours such as sleep driving, preparing and eating food, and making phone calls have been reported in association with the use of hypnotics such as suvorexant. A dose-dependant increase in suicidal ideation has been observed, especially in patients with a previous diagnosis of depression. Sleep paralysis, hypnagogic/hypnopompic hallucinations including vivid and disturbing perceptions, and mild cataplexy have also been reported. There are no adequate studies in pregnant women to ensure its safety during pregnancy or breast feeding.

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
1,2-Benzodiazepine1,2-Benzodiazepine may increase the central nervous system depressant (CNS depressant) activities of Suvorexant.
AbametapirThe serum concentration of Suvorexant can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Suvorexant can be increased when combined with Abatacept.
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Suvorexant.
AcalabrutinibThe metabolism of Acalabrutinib can be decreased when combined with Suvorexant.
Food Interactions
  • Avoid grapefruit products.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
BelsomraTablet15 mgOralMerck Ltd.2019-04-182020-05-14Canada flag
BelsomraTablet, film coated15 mg/1OralMerck Sharp & Dohme Llc2014-08-29Not applicableUS flag
BelsomraTablet5 mgOralMerck Ltd.Not applicableNot applicableCanada flag
BelsomraTablet10 mgOralMerck Ltd.2019-04-182020-05-14Canada flag
BelsomraTablet, film coated10 mg/1OralMerck Sharp & Dohme Llc2014-08-29Not applicableUS flag

Categories

ATC Codes
N05CM19 — Suvorexant
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as n,n-dialkyl-m-toluamides. These are aromatic that contain a m-toluamide, where the carboxamide group is N- substituted with two alkyl chains.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Toluenes
Direct Parent
N,N-dialkyl-m-toluamides
Alternative Parents
Phenyl-1,2,3-triazoles / Benzamides / Benzoxazoles / Dialkylarylamines / Benzoyl derivatives / 1,4-diazepanes / Aryl chlorides / Tertiary carboxylic acid amides / Oxazoles / Heteroaromatic compounds
show 7 more
Substituents
1,2,3-triazole / 1,4-diazepane / Aromatic heteropolycyclic compound / Aryl chloride / Aryl halide / Azacycle / Azole / Benzamide / Benzoic acid or derivatives / Benzoxazole
show 23 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
1,3-benzoxazoles, organochlorine compound, aromatic amide, triazoles, diazepine (CHEBI:82698)
Affected organisms
Not Available

Chemical Identifiers

UNII
081L192FO9
CAS number
1030377-33-3
InChI Key
JYTNQNCOQXFQPK-MRXNPFEDSA-N
InChI
InChI=1S/C23H23ClN6O2/c1-15-3-5-20(30-25-8-9-26-30)18(13-15)22(31)29-12-11-28(10-7-16(29)2)23-27-19-14-17(24)4-6-21(19)32-23/h3-6,8-9,13-14,16H,7,10-12H2,1-2H3/t16-/m1/s1
IUPAC Name
5-chloro-2-[(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepan-1-yl]-1,3-benzoxazole
SMILES
[H][C@@]1(C)CCN(CCN1C(=O)C1=C(C=CC(C)=C1)N1N=CC=N1)C1=NC2=C(O1)C=CC(Cl)=C2

References

General References
  1. Palasz A, Lapray D, Peyron C, Rojczyk-Golebiewska E, Skowronek R, Markowski G, Czajkowska B, Krzystanek M, Wiaderkiewicz R: Dual orexin receptor antagonists - promising agents in the treatment of sleep disorders. Int J Neuropsychopharmacol. 2014 Jan;17(1):157-68. doi: 10.1017/S1461145713000552. Epub 2013 May 23. [Article]
  2. Patel KV, Aspesi AV, Evoy KE: Suvorexant: a dual orexin receptor antagonist for the treatment of sleep onset and sleep maintenance insomnia. Ann Pharmacother. 2015 Apr;49(4):477-83. doi: 10.1177/1060028015570467. Epub 2015 Feb 9. [Article]
  3. Reddy A, Puvvada SC, Kommisetti S, El-Mallakh RS, Lippmann S: Suvorexant: something new for sleep? Acta Neuropsychiatr. 2015 Feb;27(1):53-5. doi: 10.1017/neu.2014.31. Epub 2014 Nov 14. [Article]
  4. Michelson D, Snyder E, Paradis E, Chengan-Liu M, Snavely DB, Hutzelmann J, Walsh JK, Krystal AD, Benca RM, Cohn M, Lines C, Roth T, Herring WJ: Safety and efficacy of suvorexant during 1-year treatment of insomnia with subsequent abrupt treatment discontinuation: a phase 3 randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2014 May;13(5):461-71. doi: 10.1016/S1474-4422(14)70053-5. Epub 2014 Mar 27. [Article]
  5. Howland RH: Suvorexant: a novel therapy for the treatment of insomnia. J Psychosoc Nurs Ment Health Serv. 2014 Oct;52(10):23-6. doi: 10.3928/02793695-20140924-01. [Article]
  6. FDA Approved Drug Products: BELSOMRA (suvorexant) tablets [Link]
KEGG Drug
D10082
PubChem Compound
24965990
PubChem Substance
310264985
ChemSpider
24662178
BindingDB
50318701
RxNav
1547099
ChEBI
82698
ChEMBL
CHEMBL1083659
ZINC
ZINC000049036447
PDBe Ligand
SUV
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Suvorexant
PDB Entries
4s0v / 4zj8 / 6to7 / 6tpj
FDA label
Download (403 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedBasic SciencePanic Disorder1
4CompletedTreatmentBipolar Disorder (BD) / Insomnia1
4CompletedTreatmentFatigue / Insomnia / Multiple Sclerosis1
4CompletedTreatmentHypertension / Insomnia1
4CompletedTreatmentInflammation / Insomnia / Sleep disorders and disturbances / Type 2 Diabetes Mellitus1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
TabletOral10 mg
TabletOral15 mg
TabletOral20 mg
TabletOral5 mg
Tablet, film coatedOral10 mg/1
Tablet, film coatedOral15 mg/1
Tablet, film coatedOral20 mg/1
Tablet, film coatedOral5 mg/1
Tablet, coatedOral10 mg
Tablet, coatedOral1000000 mg
Tablet, coatedOral15 mg
Tablet, coatedOral1500000 mg
Tablet, coatedOral20 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US20110195957No2011-04-192031-04-19US flag
US7951797No2011-05-312029-11-20US flag
US10098892No2018-10-162033-05-29US flag

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.117 mg/mLALOGPS
logP3.86ALOGPS
logP4.04Chemaxon
logS-3.6ALOGPS
pKa (Strongest Basic)0.25Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count5Chemaxon
Hydrogen Donor Count0Chemaxon
Polar Surface Area80.29 Å2Chemaxon
Rotatable Bond Count3Chemaxon
Refractivity134.36 m3·mol-1Chemaxon
Polarizability46.68 Å3Chemaxon
Number of Rings5Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleNoChemaxon
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/MSsplash10-0udi-0400900000-e11c4e5f401dd6810f1d
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-0udi-0423900000-ae6e62d4f4e93fc599a3
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-0002-0034900000-917be9285b6dda7ea9fc
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-0002-3227900000-b6c52c914228c660d595
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-001j-2912200000-a46050df23853a06fb60
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-001i-9112200000-636451c9ad8ddbf2b91a
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-200.43297
predicted
DeepCCS 1.0 (2019)
[M+H]+202.82854
predicted
DeepCCS 1.0 (2019)
[M+Na]+209.26195
predicted
DeepCCS 1.0 (2019)

Targets

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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. Palasz A, Lapray D, Peyron C, Rojczyk-Golebiewska E, Skowronek R, Markowski G, Czajkowska B, Krzystanek M, Wiaderkiewicz R: Dual orexin receptor antagonists - promising agents in the treatment of sleep disorders. Int J Neuropsychopharmacol. 2014 Jan;17(1):157-68. doi: 10.1017/S1461145713000552. Epub 2013 May 23. [Article]
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
References
  1. Palasz A, Lapray D, Peyron C, Rojczyk-Golebiewska E, Skowronek R, Markowski G, Czajkowska B, Krzystanek M, Wiaderkiewicz R: Dual orexin receptor antagonists - promising agents in the treatment of sleep disorders. Int J Neuropsychopharmacol. 2014 Jan;17(1):157-68. doi: 10.1017/S1461145713000552. Epub 2013 May 23. [Article]

Enzymes

Kind
Protein
Organism
Humans
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. Lee-Iannotti JK, Parish JM: Suvorexant: a promising, novel treatment for insomnia. Neuropsychiatr Dis Treat. 2016 Feb 25;12:491-5. doi: 10.2147/NDT.S31495. eCollection 2016. [Article]
  2. Rhyne DN, Anderson SL: Suvorexant in insomnia: efficacy, safety and place in therapy. Ther Adv Drug Saf. 2015 Oct;6(5):189-95. doi: 10.1177/2042098615595359. [Article]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
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

Drug created at February 23, 2015 22:11 / Updated at March 18, 2024 16:48