LEMBOREXANT

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C22H20F2N4O2
Molecular Weight	410.4166
Optical Activity	UNSPECIFIED
Defined Stereocenters	2 / 2
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

CC1=NC=C(OC[C@]2(C[C@H]2C(=O)NC3=NC=C(F)C=C3)C4=CC=CC(F)=C4)C(C)=N1

InChI

InChIKey=MUGXRYIUWFITCP-PGRDOPGGSA-N

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

HIDE SMILES / InChI

Molecular Formula	C22H20F2N4O2
Molecular Weight	410.4166
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	2 / 2
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description

Lemborexant is a dual orexin receptor antagonist, which inhibits orexin by binding competitively to two subtypes of orexin receptors. During normal periods of sleep, orexin system activity is suppressed, suggesting it is possible to purposefully facilitate the initiation and maintenance of sleep by interfering with orexin neurotransmission with lemborexant. Extensive in vitro and non-clinical testing of lemborexant supported the supposition that lemborexant has a low risk of QT prolongation at therapeutic and supratherapeutic exposures in humans. A Phase III study of lemborexant in insomnia is underway, and in addition, Eisai has announced the initiation of Phase II clinical studies of lemborexant in patients with irregular sleep-wake rhythm disorder.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
HERG 99	Inhibitor 8,504	6.1 µM [IC50]
Orexin receptor 1 8	Antagonist 2,849	6.1 nM [IC50]
Orexin receptor 2 10	Antagonist 2,849	2.6 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Insomnia 111	Primary		Phase III 665	Unknown
Irregular sleep-wake rhythm disorder 1	Primary		Phase II 1,147	Unknown

C_max

Value	Dose	Analyte	Population
22.3 ng/mL	5 mg single, oral	LEMBOREXANT plasma	Homo sapiens
22 ng/mL	5 mg 1 times / day multiple, oral	LEMBOREXANT plasma	Homo sapiens
203 ng/mL	25 mg 1 times / day steady-state, oral	LEMBOREXANT plasma	Homo sapiens

AUC

Value	Dose	Co-administered	Analyte	Population
146 ng × h/mL	5 mg single, oral		LEMBOREXANT plasma	Homo sapiens
169 ng × h/mL	5 mg 1 times / day multiple, oral		LEMBOREXANT plasma	Homo sapiens

T_1/2

Value	Dose	Analyte	Population
33.4 h	5 mg single, oral	LEMBOREXANT plasma	Homo sapiens
18 h	5 mg 1 times / day multiple, oral	LEMBOREXANT plasma	Homo sapiens
17 h	5 mg single, oral	LEMBOREXANT plasma	Homo sapiens

F_unbound

Value	Dose	Co-administered	Analyte	Population
6%	5 mg single, oral		LEMBOREXANT plasma	Homo sapiens

Doses

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Dose	Population	Adverse events
10 mg 1 times / day steady, oral Recommended	unhealthy, 55 years (range: 18 - 88 years)	Disc. AE: Somnolence, Nightmares...
5 mg 1 times / day steady, oral Recommended	unhealthy, 55 years (range: 18 - 88 years)	Disc. AE: Somnolence, Nightmares...
200 mg single, oral Highest studied dose	healthy	Other AEs: Sleep paralysis...
75 mg 1 times / day multiple, oral Highest studied dose	healthy	Other AEs: Headache, Sleep paralysis...

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AEs

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AE	Significance	Dose	Population
Palpitations	0.6% Disc. AE	10 mg 1 times / day steady, oral Recommended	unhealthy, 55 years (range: 18 - 88 years)
Nightmares	1.3% Disc. AE	10 mg 1 times / day steady, oral Recommended	unhealthy, 55 years (range: 18 - 88 years)
Somnolence	2.9% Disc. AE	10 mg 1 times / day steady, oral Recommended	unhealthy, 55 years (range: 18 - 88 years)
Nightmares	0.3% Disc. AE	5 mg 1 times / day steady, oral Recommended	unhealthy, 55 years (range: 18 - 88 years)
Somnolence	1% Disc. AE	5 mg 1 times / day steady, oral Recommended	unhealthy, 55 years (range: 18 - 88 years)

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1,946			inhibitor 2,217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP3A 227 P-gp 1,741 BCRP 910 BSEP 550 OAT1 725 OAT3 747 OATP1B1 1,079 OATP1B3 961 OCT1 620 OCT2 779 MATE1 415 MATE2 267 CYP2A6 879 CYP2C19 2,057	CYP3A5 446 P-gp 2,052 BCRP 697 OATP1B1 503 OATP1B3 435	CYP3A 142 CYP2B6 669 CYP1A2 832

Drug as perpetrator

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Target	Modality	Activity	Metabolite
BCRP 985	inhibitor 4,027	no
BCRP 985	inhibitor 4,027	no	M10 1
BSEP 554	inhibitor 4,027	no
BSEP 554	inhibitor 4,027	no	M10 1
CYP1A2 2,333	inducer 1,966	no

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Drug as victim

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Target	Modality	Activity	Metabolite	Clinical evidence
CYP3A4 1,946	substrate 4,014	major		yes (co-administration study)
CYP3A5 446	substrate 4,014	minor		yes (co-administration study)
BCRP 697	substrate 4,014	no
BCRP 697	substrate 4,014	no	M10 1
OATP1B1 503	substrate 4,014	no

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Tox targets

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Target	Modality	Metabolite
hERG 2,263	inhibitor 2,237
hERG 2,263	inhibitor 2,237	M10 1
hERG 2,263	inhibitor 2,237	M4 1
hERG 2,263	inhibitor 2,237	M9 1

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Sourcing

Sourcing

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Vendor/Aggregator	ID	URL
AA Blocks	AA0012JH	https://www.aablocks.com/goods/Goods/detail?id=AA0012JH
AbMole Bioscience	M9839	http://www.abmole.com/products/lemborexant.html
Ark Pharma Scientific Limited	A-1745	http://www.arkpharmtech.com/product/33696.html
Chem Scene	CS-4320	http://www.chemscene.com/1369764-02-2.html
Chemspace	CSSB00102527162	https://chem-space.com/CSSB00102527162

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PubMed

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Title	Date	PubMed
In Vitro and In Silico Characterization of Lemborexant (E2006), a Novel Dual Orexin Receptor Antagonist.	2017 Aug	28559480
Concentration-Response Modeling of ECG Data From Early-Phase Clinical Studies as an Alternative Clinical and Regulatory Approach to Assessing QT Risk - Experience From the Development Program of Lemborexant.	2017 Jan	27338807

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Patents

Sample Use Guides

In Vivo Use Guide

5 mg or 10 mg before the time the participant intends to try to sleep

Route of Administration: Oral

In Vitro Use Guide

The effect of lemborexant on the slow component of delayed rectifier potassium current (IKs) was examined using KCNQ1/KCNE1-CHO cells and a small, not-concentration-dependent inhibition was noted with a peak inhibitory effect of 24% at 10 (uM, and a smaller effect (13%) at 30 uM.

Substance Class	Chemical
Record UNII	0K5743G68X
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

lemborexant [INN]

Preferred Name

English

LEMBOREXANT

Official Name

English

LEMBOREXANT [JAN]

Common Name

English

DAYVIGO

Brand Name

English

(1R,2S)-2-{[(2,4-Dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide

Systematic Name

English

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Classification Tree

Code System

Code

DEA NO.

2245

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Code System

Code

Type

Description

INN

9988

PRIMARY

DAILYMED

0K5743G68X

PRIMARY

EPA CompTox

DTXSID401027940

PRIMARY

RXCUI

2272403

PRIMARY

ChEMBL

CHEMBL3545367

PRIMARY

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Related Record

Type

Details


					PUO0521HZV

CYTOCHROME P450 3A4

METABOLIC ENZYME -> SUBSTRATE

Interaction Type:

MAJOR


					0K5743G68X

LEMBOREXANT

EXCRETED UNCHANGED

Qualification:

URINE

Amount:

[<1] % (average)


					6D53G0FD0Z

PLASMA PROTEIN FRACTION (HUMAN)

BINDER->LIGAND

Comments:

Protein binding of lemborexant is approximately 93.2% to 94.0% between 29 ng/mL and 71 ng/mL.

Interaction Type:

BINDING

Amount:

[93.2 to 94] % (average)


					0UY97CSG1T

CYTOCHROME P450 2B6

METABOLIC ENZYME -> INDUCER


					246D9TQ2XG

CYTOCHROME P450 2A6

METABOLIC ENZYME -> INHIBITOR

Interaction Type:

REVERSIBLE INHIBITION

Qualification:

IC50

Amount:

7.8 MICROMOLAR (average)

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Related Record

Type

Details


					QVL1O82JI6

2-(3-FLUOROPHENYL)-N-(5-FLUORO-2-PYRIDINYL)-2-(((4-(HYDROXYMETHYL)-2-METHYL-5-PYRIMIDINYL)OXY)METHYL)CYCLOPROPANECARBOXAMIDE, (1R,2S)-

METABOLITE -> PARENT

Qualification:

PLASMA


					16B4MW9AWJ

CYCLOPROPANECARBOXAMIDE, 2-(((2,4-DIMETHYL-5-PYRIMIDINYL)OXY)METHYL)-2-(5-FLUORO-2-HYDROXYPHENYL)-N-(5-FLUORO-2-PYRIDINYL)-, (1R,2S)-

METABOLITE -> PARENT

Qualification:

PLASMA


					Q86TE42WCP

CYCLOPROPANECARBOXAMIDE, 2-(((2,4-DIMETHYL-1-OXIDO-5-PYRIMIDINYL)OXY)METHYL)-2-(3-FLUOROPHENYL)-N-(5-FLUORO-2-PYRIDINYL)-, (1R,2S)-

METABOLITE -> PARENT

Qualification:

PLASMA


					HFA1OCI6NI

CYCLOPROPANECARBOXAMIDE, 2-(((2,6-DIMETHYL-1-OXIDO-5-PYRIMIDINYL)OXY)METHYL)-2-(3-FLUOROPHENYL)-N-(5-FLUORO-2-PYRIDINYL)-, (1R,2S)-

METABOLITE -> PARENT

Interaction Type:

MAJOR

Qualification:

PLASMA


					UO0G8EEV0T

CYCLOPROPANECARBOXAMIDE, 2-(3-FLUOROPHENYL)-N-(5-FLUORO-2-PYRIDINYL)-2-(((2-(HYDROXYMETHYL)-4-METHYL-5-PYRIMIDINYL)OXY)METHYL)-, (1R,2S)-

METABOLITE -> PARENT

Qualification:

PLASMA

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Related Record

Type

Details


					0K5743G68X

LEMBOREXANT

ACTIVE MOIETY

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Name	Property Type	Amount	Parameters
Volume of Distribution	PHARMACOKINETIC	1970 LITERS (average)

Biological Half-life	PHARMACOKINETIC	18 hours [17 to 19] (average)	ORAL ADMINISTRATION

Tmax	PHARMACOKINETIC	[3 to 5] hours (average)	HIGH-FAT AND HIGH-CALORIE MEAL FED CONDITION

Tmax	PHARMACOKINETIC	[1 to 3] hours (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

Tox targets

Sourcing

PubMed

Patents

Sample Use Guides

C_max

T_1/2

F_unbound

Drug as perpetrator