Identification

Name
Suvorexant
Accession Number
DB09034
Type
Small Molecule
Groups
Approved, Investigational
Description

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.

Structure
Thumb
Synonyms
  • [(7R)-4-(5-Chlor-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanon
  • [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone
  • [(7R)-4-(5-Chloro-1,3-benzoxazol-2-yl)-7-méthyl-1,4-diazépan-1-yl][5-méthyl-2-(2H-1,2,3-triazol-2-yl)phényl]méthanone
  • [(7R)-4-(5-chlorobenzoxazol-2-yl)-7-methylhexahydro-1H-1,4-diazepin-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone
External IDs
MFCD18251525 / MK 4305 / MK-4305 / MK4305
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
BelsomraTablet, film coated20 mg/1OralMerck Sharp & Dohme Limited2014-08-29Not applicableUs
BelsomraTablet, film coated5 mg/1OralMerck Sharp & Dohme Limited2014-08-29Not applicableUs
BelsomraTablet, film coated15 mg/1OralMerck Sharp & Dohme Limited2014-08-29Not applicableUs
BelsomraTablet, film coated10 mg/1OralMerck Sharp & Dohme Limited2014-08-29Not applicableUs
Categories
UNII
081L192FO9
CAS number
1030377-33-3
Weight
Average: 450.93
Monoisotopic: 450.1571017
Chemical Formula
C23H23ClN6O2
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

Pharmacology

Indication

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

Associated Conditions
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
Human
AOrexin receptor type 2
antagonist
Human
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.

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
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.

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

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of Suvorexant can be decreased when combined with (R)-warfarin.
(S)-WarfarinThe metabolism of (S)-Warfarin can be decreased when combined with Suvorexant.
2,5-Dimethoxy-4-ethylthioamphetamine2,5-Dimethoxy-4-ethylthioamphetamine may increase the central nervous system depressant (CNS depressant) activities of Suvorexant.
3,4-Methylenedioxyamphetamine3,4-Methylenedioxyamphetamine may increase the central nervous system depressant (CNS depressant) activities of Suvorexant.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Suvorexant.
4-Bromo-2,5-dimethoxyamphetamine4-Bromo-2,5-dimethoxyamphetamine may increase the central nervous system depressant (CNS depressant) activities of Suvorexant.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Suvorexant.
4-Methoxyamphetamine4-Methoxyamphetamine may increase the central nervous system depressant (CNS depressant) activities of Suvorexant.
5-androstenedioneThe metabolism of Suvorexant can be decreased when combined with 5-androstenedione.
5-methoxy-N,N-dimethyltryptamine5-methoxy-N,N-dimethyltryptamine may increase the central nervous system depressant (CNS depressant) activities of Suvorexant.
Food Interactions
  • Grapefruit Juice

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. [PubMed:23702225]
  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. [PubMed:25667197]
  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. [PubMed:25397996]
  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. [PubMed:24680372]
  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. [PubMed:25291725]
External Links
KEGG Drug
D10082
PubChem Compound
24965990
PubChem Substance
310264985
ChemSpider
24662178
BindingDB
50318701
ChEBI
82698
ChEMBL
CHEMBL1083659
HET
SUV
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Suvorexant
PDB Entries
4s0v / 4zj8
FDA label
Download (403 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0RecruitingBasic SciencePanic Disorders1
1CompletedTreatmentHepatic Insufficiency / Sleeplessness1
1CompletedTreatmentInsomnia Disorders1
1CompletedTreatmentSleep Apnea Syndrome1
1CompletedTreatmentSleeplessness3
1RecruitingTreatmentHealthy Recreational Drug Users1
2CompletedTreatmentPrimary Insomnia1
2RecruitingTreatmentCocaine Use Disorders / Feeling Anxious1
2, 3Enrolling by InvitationTreatmentCortisol; Hypersecretion / Craving / Sleep Disturbances1
3CompletedTreatmentAlzheimer's Disease (AD) / Sleeplessness1
3CompletedTreatmentPrimary Insomnia2
3CompletedTreatmentSleeplessness1
3RecruitingTreatmentHemophilia A / Hereditary factor IX deficiency1
4Not Yet RecruitingTreatmentDepression / Major Depressive Disorder (MDD) / Sleeplessness1
4Not Yet RecruitingTreatmentSleep Initiation and Maintenance Disorders / Stress Disorders, Posttraumatic1
4Not Yet RecruitingTreatmentSleeplessness1
4RecruitingTreatmentBipolar Disorder (BD) / Sleeplessness1
4RecruitingTreatmentDisseminated Sclerosis / Sleeplessness / Tiredness1
4RecruitingTreatmentHigh Blood Pressure (Hypertension) / Sleeplessness1
4RecruitingTreatmentPosttraumatic Stress Disorders1
4RecruitingTreatmentPosttraumatic Stress Disorders / Sleeplessness1
4RecruitingTreatmentSleep Disorder, Shift-Work1
4RecruitingTreatmentSleeplessness2
4TerminatedTreatmentFibromyalgia / Sleeplessness1
Not AvailableCompletedNot AvailableHemorrhage1
Not AvailableRecruitingOtherAmyloid-beta1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Tablet, film coatedOral10 mg/1
Tablet, film coatedOral15 mg/1
Tablet, film coatedOral20 mg/1
Tablet, film coatedOral5 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US20110195957No2011-04-192031-04-19Us
US7951797No2009-11-202029-11-20Us

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/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,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
N,n-dialkyl-m-toluamide / Phenyltriazole / Phenyl-1,2,3-triazole / Benzamide / Benzoic acid or derivatives / Benzoxazole / Benzoyl / Dialkylarylamine / 1,4-diazepane / Diazepane
show 23 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
1,3-benzoxazoles, organochlorine compound, aromatic amide, triazoles, diazepine (CHEBI:82698)

Targets

Kind
Protein
Organism
Human
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. [PubMed:23702225]
Kind
Protein
Organism
Human
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. [PubMed:23702225]

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. 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. [PubMed:26955275]
  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. [PubMed:26478806]

Drug created on February 23, 2015 15:11 / Updated on November 02, 2018 06:57