Suvorexant

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C23H23ClN6O2
Molecular Weight	450.921
Optical Activity	( - )
Defined Stereocenters	1 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

C[C@@H]1CCN(CCN1C(=O)C2=CC(C)=CC=C2N3N=CC=N3)C4=NC5=C(O4)C=CC(Cl)=C5

InChI

InChIKey=JYTNQNCOQXFQPK-MRXNPFEDSA-N

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

HIDE SMILES / InChI

Molecular Formula	C23H23ClN6O2
Molecular Weight	450.921
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	1 / 1
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description

Suvorexant is a selective dual antagonist of orexin receptors OX1R and OX2R. It has been approved for the treatment of insomnia. The mechanism by which suvorexant exerts its therapeutic effect in insomnia is presumed to be through antagonism of orexin receptors. The orexin neuropeptide signaling system is a central promoter of wakefulness. Blocking the binding of wake-promoting neuropeptides orexin A and orexin B to receptors OX1R and OX2R is thought to suppress wake drive.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Orexin receptor type 2 3	Antagonist 2,849		0.55 nM [Ki]
Orexin receptor type 1 3	Antagonist 2,849		0.35 nM [Ki]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Sleep-onset insomnia 3	Palliative		Approved 8,583	BELSOMRA

C_max

Value	Dose	Analyte	Population
0.854 uM	20 mg single, oral	SUVOREXANT plasma	Homo sapiens
0.356 μM	10 mg single, oral	SUVOREXANT plasma	Homo sapiens
0.572 μM	20 mg single, oral	SUVOREXANT plasma	Homo sapiens
0.802 μM	40 mg single, oral	SUVOREXANT plasma	Homo sapiens
1.329 μM	80 mg single, oral	SUVOREXANT plasma	Homo sapiens
1.425 μM	100 mg single, oral	SUVOREXANT plasma	Homo sapiens
0.414 μM	10 mg 1 times / day steady-state, oral	SUVOREXANT plasma	Homo sapiens
0.574 μM	20 mg 1 times / day steady-state, oral	SUVOREXANT plasma	Homo sapiens
1.08 μM	40 mg 1 times / day steady-state, oral	SUVOREXANT plasma	Homo sapiens
1.488 μM	80 mg 1 times / day steady-state, oral	SUVOREXANT plasma	Homo sapiens
2.085 μM	100 mg 1 times / day steady-state, oral	SUVOREXANT plasma	Homo sapiens

AUC

Value	Dose	Analyte	Population
3.43 μM × h	10 mg single, oral	SUVOREXANT plasma	Homo sapiens
5.03 μM × h	20 mg single, oral	SUVOREXANT plasma	Homo sapiens
8.53 μM × h	40 mg single, oral	SUVOREXANT plasma	Homo sapiens
11.48 μM × h	80 mg single, oral	SUVOREXANT plasma	Homo sapiens
18.1 μM × h	100 mg single, oral	SUVOREXANT plasma	Homo sapiens
4.36 μM × h	10 mg 1 times / day steady-state, oral	SUVOREXANT plasma	Homo sapiens
6.08 μM × h	20 mg 1 times / day steady-state, oral	SUVOREXANT plasma	Homo sapiens
10.64 μM × h	40 mg 1 times / day steady-state, oral	SUVOREXANT plasma	Homo sapiens
18.32 μM × h	80 mg 1 times / day steady-state, oral	SUVOREXANT plasma	Homo sapiens
27.62 μM × h	100 mg 1 times / day steady-state, oral	SUVOREXANT plasma	Homo sapiens

T_1/2

Value	Dose	Analyte	Population
7.7 h	10 mg single, oral	SUVOREXANT plasma	Homo sapiens
8.4 h	20 mg single, oral	SUVOREXANT plasma	Homo sapiens
8.6 h	40 mg single, oral	SUVOREXANT plasma	Homo sapiens
10 h	80 mg single, oral	SUVOREXANT plasma	Homo sapiens
12.6 h	100 mg single, oral	SUVOREXANT plasma	Homo sapiens
8.1 h	10 mg 1 times / day steady-state, oral	SUVOREXANT plasma	Homo sapiens
9.2 h	20 mg 1 times / day steady-state, oral	SUVOREXANT plasma	Homo sapiens
9.4 h	40 mg 1 times / day steady-state, oral	SUVOREXANT plasma	Homo sapiens
11.2 h	80 mg 1 times / day steady-state, oral	SUVOREXANT plasma	Homo sapiens
14.5 h	100 mg 1 times / day steady-state, oral	SUVOREXANT plasma	Homo sapiens
12 h		SUVOREXANT plasma	Homo sapiens

F_unbound

Value	Dose	Co-administered	Analyte	Population
1%			SUVOREXANT plasma	Homo sapiens

Doses

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Dose	Population	Adverse events
100 mg 1 times / day steady, oral Highest studied dose	healthy, 34.3 years(range: 19–45 years)	Other AEs: Somnolence, Fatigue...

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AEs

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AE	Significance	Dose	Population
Insomnia	17%	100 mg 1 times / day steady, oral Highest studied dose	healthy, 34.3 years(range: 19–45 years)
Dizziness	33%	100 mg 1 times / day steady, oral Highest studied dose	healthy, 34.3 years(range: 19–45 years)
Phlebitis	33%	100 mg 1 times / day steady, oral Highest studied dose	healthy, 34.3 years(range: 19–45 years)
Somnolence	67%	100 mg 1 times / day steady, oral Highest studied dose	healthy, 34.3 years(range: 19–45 years)
Fatigue	83%	100 mg 1 times / day steady, oral Highest studied dose	healthy, 34.3 years(range: 19–45 years)

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inducer 1,087 substrate 1,946 inhibitor 2,252	inducer 440 inhibitor 2,438	inhibitor 2,507

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP3A 227 P-gp 1,741 CYP1A2 2,153 CYP2B6 926 CYP2C8 1,057 CYP2C19 2,057 OATP1B1 1,079 BCRP 910 OCT2 779	CYP2C19 1,119 P-gp 2,052 CYP3A 220	CYP1A2 832

Drug as perpetrator

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Target	Modality	Activity	Metabolite
CYP2C19 2,141	inhibitor 4,027	no [IC50 5.3 uM]
CYP1A2 2,333	inhibitor 4,027	no [IC50 >100 uM]	L-002015883 3
CYP3A 317	inhibitor 4,027	no	L-002015883 3
CYP3A4 2,633	inhibitor 4,027	weak [IC50 11 uM]	L-002015883 3
CYP2C8 1,117	inhibitor 4,027	weak [IC50 15 uM]

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Drug as victim

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Target	Modality	Activity	Metabolite
CYP2C19 1,119	substrate 4,014	minor
CYP3A 220	substrate 4,014	yes
CYP3A4 1,946	substrate 4,014	yes
P-gp 2,052	substrate 4,014	yes	L-002015883 3

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Sourcing

Sourcing

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Vendor/Aggregator	ID	URL
ChEBI	CHEBI:82698	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:82698
ChemicalBook	CB62589660	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB62589660
ChemicalBook	CB92599932	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB92599932
ZINC	ZINC000049036447	http://zinc15.docking.org/substances/ZINC000049036447

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PubMed

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Title	Date	PubMed
Promotion of sleep by suvorexant-a novel dual orexin receptor antagonist.	2011 Mar	21473737
The hypocretins/orexins: integrators of multiple physiological functions.	2014 Jan	24102345
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.	2014 May	24680372
Suvorexant: a dual orexin receptor antagonist for the treatment of sleep onset and sleep maintenance insomnia.	2015 Apr	25667197
Suvorexant: something new for sleep?	2015 Feb	25397996

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Patents

Sample Use Guides

In Vivo Use Guide

The recommended dose for BELSOMRA (suvorexant) is 10 mg, taken no more than once per night and within 30 minutes of going to bed, with at least 7 hours remaining before the planned time of awakening. If the 10 mg dose is well-tolerated but not effective, the dose can be increased. The maximum recommended dose of BELSOMRA is 20 mg once daily

Route of Administration: Oral

In Vitro Use Guide

Examination of Suvorexant in radioligand binding assays using tissue from transgenic rats expressing the human OX2R found nearly full receptor occupancy (>90%) at plasma exposures of 1.1 μM.

Substance Class	Chemical
Record UNII	081L192FO9
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

Suvorexant

Official Name

English

Suvorexant [INN]

Preferred Name

English

BELSOMRA COMPONENT SUVOREXANT

Brand Name

English

Suvorexant [JAN]

Common Name

English

Methanone, [(7R)-4-(5-chloro-2-benzoxazolyl)hexahydro-7-methyl-1H-1,4-diazepin-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]-

Systematic Name

English

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Classification Tree

Code System

Code

Other hypnotics and sedatives

WHO-ATC

N05CM19

Sec. 1308.11 Schedule IV.

DEA NO.

2223

Established Pharmacologic Class

NDF-RT

N0000191000

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Code System

Code

Type

Description

EVMPD

SUB180101

PRIMARY

EPA CompTox

DTXSID90145616

PRIMARY

IUPHAR

2890

PRIMARY

ChEMBL

CHEMBL1083659

PRIMARY

NDF-RT

N0000185503

PRIMARY

P-Glycoprotein Inhibitors [MoA]

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Related Record

Type

Details


					AD890S9AKZ

OREXIN RECEPTOR TYPE 2

TARGET -> INHIBITOR

Amount:


					5D3S2VQZ54

SUVOREXANT HYDROCHLORIDE

SALT/SOLVATE -> PARENT

Amount:


					D8K8NA4KCA

OREXIN RECEPTOR TYPE 1

TARGET -> INHIBITOR

Amount:


					6D53G0FD0Z

PLASMA PROTEIN FRACTION (HUMAN)

BINDER->LIGAND

Interaction Type:

BINDING

Amount:

[>99] % (average)


					081I12ZA58

CYTOCHROME P450 2C19

METABOLIC ENZYME -> SUBSTRATE

Interaction Type:

MINOR

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Related Record

Type

Details


					BQ3ZED7JDX

((7S)-4-(5-CHLORO-1,3-BENZOXAZOL-2-YL)-7-(HYDROXYMETHYL)-1,4-DIAZEPAN-1-YL)-(5-METHYL-2-(TRIAZOL-2-YL)PHENYL)METHANONE

METABOLITE -> PARENT

Comments:

In plasma, M10A was the minor metabolite. In feces, M10A was accounted for 9% of dose.

Qualification:

FECAL; PLASMA


					G8R68A764K

3-(((7R)-4-(5-CHLORO-1,3-BENZOXAZOL-2-YL)-7-METHYL-1,4-DIAZEPAN-1-YL)CARBONYL)-4-(2H-1,2,3-TRIAZOL-2-YL)BENZOIC ACID

METABOLITE -> PARENT

Comments:

M4 was the minor metabolite in plasma, but M4 was the major metabolite in urine and feces, accounting for 4.1% and 17.0% of the dose, respectively.

Qualification:

FECAL; PLASMA; URINE

Amount:


					85BCK54NR7

((7R)-4-(6-HYDROXY-1,3-BENZOXAZOL-2-YL)-7-METHYL-1,4-DIAZEPAN-1-YL)-(5-METHYL-2-(TRIAZOL-2-YL)PHENYL)METHANONE

METABOLITE -> PARENT

Qualification:

PLASMA

Amount:

4.8 % (average)


					V5V4BX93AT

(3-(((7R)-4-(5-CHLORO-1,3-BENZOXAZOL-2-YL)-7-METHYL-1,4-DIAZEPAN-1-YL)CARBONYL)-4-(2H-1,2,3-TRIAZOL-2-YL)PHENYL)METHANOL

METABOLITE -> PARENT

Interaction Type:

MAJOR

Qualification:

PLASMA

Amount:

36.5 % (average)


					7Z8T8DJW5C

((7R)-4-(6-HYDROXY-1,3-BENZOXAZOL-2-YL)-7-METHYL-1,4-DIAZEPAN-1-YL)-(5-(HYDROXYMETHYL)-2-(TRIAZOL-2-YL)PHENYL)METHANONE

METABOLITE -> PARENT

Interaction Type:

MINOR

Qualification:

PLASMA

Amount:

3.3 % (average)

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Related Record

Type

Details


					081L192FO9

Suvorexant

ACTIVE MOIETY

Amount:

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Name	Property Type	Amount
Biological Half-life	PHARMACOKINETIC	12 hours (average)

Tmax	PHARMACOKINETIC	2 hours [0.5 to 6] (average)

Volume of Distribution	PHARMACOKINETIC	0.7 Liters/Kilogram (average)

SMILES

InChI

CNS Activity

Originator

Approval Year

Targets

Conditions

Cmax

AUC

T1/2

Funbound

Doses

AEs

Overview

OverviewOther

Drug as perpetrator​

Drug as victim

Sourcing

PubMed

Patents

Sample Use Guides

C_max

T_1/2

F_unbound

Drug as perpetrator