DARIDOREXANT

Details

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

SHOW SMILES / InChI

SMILES

COC1=CC(C(=O)N2CCC[C@@]2(C)C3=NC4=C(C)C(Cl)=CC=C4N3)=C(C=C1)N5N=CC=N5

InChI

InChIKey=NBGABHGMJVIVBW-QHCPKHFHSA-N

InChI=1S/C23H23ClN6O2/c1-14-17(24)6-7-18-20(14)28-22(27-18)23(2)9-4-12-29(23)21(31)16-13-15(32-3)5-8-19(16)30-25-10-11-26-30/h5-8,10-11,13H,4,9,12H2,1-3H3,(H,27,28)/t23-/m0/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

Daridorexant (Quviviq™; Idorsia Pharmaceuticals Ltd.) is an orally administered dual orexin type 1 and type 2 (OX1 and OX2) receptor antagonist (DORA) being developed for the treatment of insomnia. It was selected from a pool of drug candidates on the basis of an expected effect duration of ≈ 8 h at a dose of 25 mg, with a half-life intended to minimize residual effects that might impair daytime functioning. Based on the results of two pivotal phase III trials, daridorexant was recently approved in the USA for the treatment of adult patients with insomnia characterized by difficulties with sleep onset and/or sleep maintenance. The mechanism of action of daridorexant in the treatment of insomnia is presumed to be through antagonism of orexin receptors. The orexin neuropeptide signaling system plays a role in 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

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Orexin receptor 1	Antagonist		8.8 null [pKi]
Orexin receptor 2	Antagonist		8.9 null [pKi]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Insomnia	Primary		Approved	QUVIVIQ

C_max

Value	Dose	Analyte	Population
954.68 ng/mL	50 mg 1 times / day steady-state, oral	DARIDOREXANT plasma	Homo sapiens
160 ng/mL	5 mg single, oral	DARIDOREXANT plasma	Homo sapiens
632 ng/mL	25 mg single, oral	DARIDOREXANT plasma	Homo sapiens
1231 ng/mL	50 mg single, oral	DARIDOREXANT plasma	Homo sapiens
1557 ng/mL	100 mg single, oral	DARIDOREXANT plasma	Homo sapiens
1869 ng/mL	200 mg single, oral	DARIDOREXANT plasma	Homo sapiens
256 ng/mL	10 mg 1 times / day multiple, oral	DARIDOREXANT plasma	Homo sapiens
280 ng/mL	10 mg 1 times / day multiple, oral	DARIDOREXANT plasma	Homo sapiens
614 ng/mL	25 mg 1 times / day multiple, oral	DARIDOREXANT plasma	Homo sapiens
616 ng/mL	25 mg 1 times / day multiple, oral	DARIDOREXANT plasma	Homo sapiens
1225 ng/mL	75 mg 1 times / day multiple, oral	DARIDOREXANT plasma	Homo sapiens
1308 ng/mL	75 mg 1 times / day multiple, oral	DARIDOREXANT plasma	Homo sapiens

AUC

Value	Dose	Analyte	Population
9981.47 ng × h/mL	50 mg 1 times / day steady-state, oral	DARIDOREXANT plasma	Homo sapiens
894 ng × h/mL	5 mg single, oral	DARIDOREXANT plasma	Homo sapiens
2568 ng × h/mL	25 mg single, oral	DARIDOREXANT plasma	Homo sapiens
6947 ng × h/mL	50 mg single, oral	DARIDOREXANT plasma	Homo sapiens
10998 ng × h/mL	100 mg single, oral	DARIDOREXANT plasma	Homo sapiens
17864 ng × h/mL	200 mg single, oral	DARIDOREXANT plasma	Homo sapiens
1156 ng × h/mL	10 mg 1 times / day multiple, oral	DARIDOREXANT plasma	Homo sapiens
1293 ng × h/mL	10 mg 1 times / day multiple, oral	DARIDOREXANT plasma	Homo sapiens
3502 ng × h/mL	25 mg 1 times / day multiple, oral	DARIDOREXANT plasma	Homo sapiens
3805 ng × h/mL	25 mg 1 times / day multiple, oral	DARIDOREXANT plasma	Homo sapiens
8583 ng × h/mL	75 mg 1 times / day multiple, oral	DARIDOREXANT plasma	Homo sapiens
8940 ng × h/mL	75 mg 1 times / day multiple, oral	DARIDOREXANT plasma	Homo sapiens

T_1/2

Value	Dose	Analyte	Population
8 h	50 mg 1 times / day steady-state, oral	DARIDOREXANT plasma	Homo sapiens
6.5 h	5 mg single, oral	DARIDOREXANT plasma	Homo sapiens
6.1 h	25 mg single, oral	DARIDOREXANT plasma	Homo sapiens
5.9 h	50 mg single, oral	DARIDOREXANT plasma	Homo sapiens
7.5 h	100 mg single, oral	DARIDOREXANT plasma	Homo sapiens
8.8 h	200 mg single, oral	DARIDOREXANT plasma	Homo sapiens
5.9 h	10 mg 1 times / day multiple, oral	DARIDOREXANT plasma	Homo sapiens
5.6 h	10 mg 1 times / day multiple, oral	DARIDOREXANT plasma	Homo sapiens
5.9 h	25 mg 1 times / day multiple, oral	DARIDOREXANT plasma	Homo sapiens
6.7 h	25 mg 1 times / day multiple, oral	DARIDOREXANT plasma	Homo sapiens
9.2 h	75 mg 1 times / day multiple, oral	DARIDOREXANT plasma	Homo sapiens
8.5 h	75 mg 1 times / day multiple, oral	DARIDOREXANT plasma	Homo sapiens

F_unbound

Value	Dose	Co-administered	Analyte	Population
0.3%			DARIDOREXANT plasma	Homo sapiens

Doses

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Dose	Population	Adverse events
50 mg 1 times / day steady, oral Recommended\|Highest studied dose	unhealthy	Disc. AE: Supraventricular extrasystoles, Renal Impairment...
25 mg 1 times / day steady, oral Recommended\|Studied dose	unhealthy	Disc. AE: colitis ulcerative, sedation...

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AEs

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AE	Significance	Dose	Population
Renal Impairment	1 patient Disc. AE	50 mg 1 times / day steady, oral Recommended\|Highest studied dose	unhealthy
Supraventricular extrasystoles	1 patient Disc. AE	50 mg 1 times / day steady, oral Recommended\|Highest studied dose	unhealthy
colitis ulcerative	1 patient Disc. AE	25 mg 1 times / day steady, oral Recommended\|Studied dose	unhealthy
depressed mood	1 patient Disc. AE	25 mg 1 times / day steady, oral Recommended\|Studied dose	unhealthy
poor quality sleep	1 patient Disc. AE	25 mg 1 times / day steady, oral Recommended\|Studied dose	unhealthy

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate inhibitor inducer	inhibitor substrate inducer	inhibitor substrate	inhibitor

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP2C19 CYP1A2 CYP2C8 CYP2B6 CYP2A6 MATE2-K MATE1 OATP1B1 OATP1B3 OAT3 P-gp OCT1 BCRP	OATP1B3 P-gp CYP1A2 CYP2C8 CYP2C19 BCRP OATP1B1	CYP1A2 CYP2B6

Drug as perpetrator

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Target	Modality	Activity	Metabolite
CYP1A2	inhibitor	no [IC50 >44 uM]	M1
CYP2B6	inhibitor	no [IC50 >44 uM]	M1
CYP2D6	inhibitor	no [IC50 >44 uM]	M1
CYP1A2	inhibitor	no [IC50 >=50 uM]
CYP2A6	inhibitor	no [IC50 >=50 uM]

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Drug as victim

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Target	Modality	Activity	Clinical evidence
CYP3A4	substrate	major	yes (co-administration study)
CYP1A2	substrate	minor
CYP2C19	substrate	minor
CYP2C8	substrate	minor
CYP2C9	substrate	minor

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Tox targets

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Target	Modality	Activity	Metabolite	Clinical evidence
hERG	inhibitor

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PubMed

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Title	Date	PubMed
Daridorexant for the Treatment of Insomnia.	2022	36045942
Daridorexant: First Approval.	2022 Apr	35298826

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Patents

Sample Use Guides

In Vivo Use Guide

The recommended dosage is 25 mg to 50 mg once per night, taken orally within 30 minutes before going to bed, with at least 7 hours remaining prior to planned awakening.

Route of Administration: Oral

In Vitro Use Guide

The Kb values were established as 1.1 nM in a rat, 0.3 nM in dog and 0.5 nM in human models with OX1r and 1.7, 0.7 and 0.8 nM for OX2r for rat, dog and human, respectively, in calcium release assays.

Substance Class	Chemical
Record UNII	LMQ24G57E9
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

DARIDOREXANT

Official Name

English

(2S)-2-(5-CHLORO-4-METHYL-1H-BENZIMIDAZOL-2-YL)-2-METHYLPYRROLIDIN-1-YL)(5-METHOXY-2-(2H-1,2,3-TRIAZOL-2-YL)PHENYL)METHANONE

Systematic Name

English

DARIDOREXANT [USAN]

Common Name

English

ACT-541468

Code

English

NEMOREXANT

Common Name

English

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Classification Tree

Code System

Code

Sec. 1308.11 Schedule V.

DEA NO.

2410

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Code System

Code

Type

Description

NCI_THESAURUS

C174674

PRIMARY

EPA CompTox

DTXSID701336356

PRIMARY

SMS_ID

300000005922

PRIMARY

RXCUI

2591497

PRIMARY

INN

10679

PRIMARY

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DARIDOREXANT HYDROCHLORIDE

SALT/SOLVATE -> PARENT

Amount:

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Related Record

Type

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					LMQ24G57E9

DARIDOREXANT

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Amount:

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SMILES

InChI

CNS Activity

Approval Year

Targets

Conditions

Cmax

AUC

T1/2

Funbound

Doses

AEs

Overview

OverviewOther

Drug as perpetrator​

Drug as victim

Tox targets

PubMed

Patents

Sample Use Guides

C_max

T_1/2

F_unbound

Drug as perpetrator