UPADACITINIB

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C17H19F3N6O
Molecular Weight	380.3676
Optical Activity	UNSPECIFIED
Defined Stereocenters	2 / 2
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

CC[C@@H]1CN(C[C@@H]1C2=CN=C3C=NC4=C(C=CN4)N23)C(=O)NCC(F)(F)F

InChI

InChIKey=WYQFJHHDOKWSHR-MNOVXSKESA-N

InChI=1S/C17H19F3N6O/c1-2-10-7-25(16(27)24-9-17(18,19)20)8-11(10)13-5-22-14-6-23-15-12(26(13)14)3-4-21-15/h3-6,10-11,21H,2,7-9H2,1H3,(H,24,27)/t10-,11+/m1/s1

HIDE SMILES / InChI

Molecular Formula	C17H19F3N6O
Molecular Weight	380.3676
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

Upadacitinib (ABT-494) is a Janus kinase 1 (JAK1) inhibitor currently being developed by AbbVie for the treatment of rheumatoid arthritis (RA), Crohn’s disease, ulcerative colitis, atopic dermatitis, and psoriatic arthritis. It is also being investigated as a potential treatment for people with active ankylosing spondylitis (AS). Currently, upadacitinib is being evaluatedin six global phase III studies in RA and twophase III studies in psoriatic arthritis (PsA), inaddition to phase II studies in Crohn’s disease and atopicdermatitis and a combined phase II/III study inulcerative colitis. Upadacitinib is a potent and selective Janus kinase (JAK) 1 inhibitor with an IC50 of 43 nM.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Tyrosine-protein kinase JAK1 39	Inhibitor 8,504		43.0 nM [IC50]
Tyrosine-protein kinase JAK2 59	Inhibitor 8,504		200.0 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Rheumatoid arthritis 320	Primary		Approved 8,583	RINVOQ

C_max

Value	Dose	Co-administered	Analyte	Population
63.7 ng/mL	30 mg single, oral		UPADACITINIB plasma	Homo sapiens

AUC

Value	Dose	Co-administered	Analyte	Population
491 ng × h/mL	30 mg single, oral		UPADACITINIB plasma	Homo sapiens

T_1/2

Value	Dose	Co-administered	Analyte	Population
18.1 h	30 mg single, oral		UPADACITINIB plasma	Homo sapiens

F_unbound

Value	Dose	Co-administered	Analyte	Population
48%			UPADACITINIB plasma	Homo sapiens

Doses

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Dose	Population	Adverse events
30 mg 1 times / day steady, oral Highest studied dose	unhealthy, 39.9 years (range: 18-75 years)	Other AEs: Anemia, Neutropenia...
15 mg 1 times / day steady, oral Recommended	unhealthy, adult	Other AEs: Adverse event...
15 mg 1 times / day steady, oral Recommended	unhealthy, adult	Disc. AE: Anemia, Vertigo...

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AEs

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AE	Significance	Dose	Population
Acne	14%	30 mg 1 times / day steady, oral Highest studied dose	unhealthy, 39.9 years (range: 18-75 years)
Anemia	2.4%	30 mg 1 times / day steady, oral Highest studied dose	unhealthy, 39.9 years (range: 18-75 years)
Neutropenia	4.8%	30 mg 1 times / day steady, oral Highest studied dose	unhealthy, 39.9 years (range: 18-75 years)
Nasopharyngitis	7.1%	30 mg 1 times / day steady, oral Highest studied dose	unhealthy, 39.9 years (range: 18-75 years)
Nausea	7.1%	30 mg 1 times / day steady, oral Highest studied dose	unhealthy, 39.9 years (range: 18-75 years)

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1,946 inhibitor 2,252	inhibitor 2,438	substrate 1,388 inhibitor 2,507	inhibitor 2,217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 2,153 CYP2B6 926 CYP2C19 2,057 P-gp 1,741 BCRP 910 BSEP 550 OATP1B1 1,079 OATP1B3 961 OCT1 620 OCT2 779 OAT1 725 OAT3 747 MATE1 415 MATE2 267	CYP3A5 446 P-gp 2,052 BCRP 697 OATP1B1 503 OATP1B3 435 OCT1 393	CYP1A2 832 CYP2B6 669 CYP3A 142

Drug as perpetrator

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Target	Modality	Activity	Clinical evidence
CYP1A2 2,333	inducer 1,966	minor
CYP3A4 2,633	inhibitor 4,027	no [IC50 181 uM]	weak (co-administration study)
CYP2C9 2,497	inhibitor 4,027	no [IC50 40.3 uM]	no (co-administration study)
CYP2C19 2,141	inhibitor 4,027	no [IC50 >250 uM]	no (co-administration study)
CYP2D6 2,546	inhibitor 4,027	no [IC50 >250 uM]	no (co-administration study)

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Drug as victim

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Target	Modality	Activity	Clinical evidence
CYP3A4 1,946	substrate 4,014	major	yes (co-administration study)
CYP2D6 1,388	substrate 4,014	minor
CYP3A5 446	substrate 4,014	minor
OATP1B3 435	substrate 4,014	no
OCT1 393	substrate 4,014	no

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Tox targets

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Target	Modality	Activity	Metabolite	Clinical evidence
hERG 2,263	inhibitor 2,237

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Sourcing

Sourcing

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Vendor/Aggregator	ID	URL
AA Blocks	AA01E0RQ	https://www.aablocks.com/goods/Goods/detail?id=AA01E0RQ
Aaron Chemicals	AR01E1JI	http://www.aaronchem.com/1310726-60-3
abcr GmbH	AB514878	http://www.abcr.com/shop/en/AB514878
Achemtek	0102-032615	http://achemtek.com/1310726-60-3-2
Acorn PharmaTech	ACN-052823	http://www.acornpharmatech.com/

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PubMed

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Title	Date	PubMed
Efficacy and Safety of ABT-494, a Selective JAK-1 Inhibitor, in a Phase IIb Study in Patients With Rheumatoid Arthritis and an Inadequate Response to Methotrexate.	2016 Dec	27390150
A Phase IIb Study of ABT-494, a Selective JAK-1 Inhibitor, in Patients With Rheumatoid Arthritis and an Inadequate Response to Anti-Tumor Necrosis Factor Therapy.	2016 Dec	27389975
Pharmacokinetics, Safety and Tolerability of ABT-494, a Novel Selective JAK 1 Inhibitor, in Healthy Volunteers and Subjects with Rheumatoid Arthritis.	2016 Dec	27272171
Population Pharmacokinetics of Upadacitinib in Healthy Subjects and Subjects with Rheumatoid Arthritis: Analyses of Phase I and II Clinical Trials.	2018 Aug	29076110

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Patents

Sample Use Guides

In Vivo Use Guide

The recommended dose of RINVOQ (Upadacitinib) is 15 mg once daily.

Route of Administration: Oral

In Vitro Use Guide

Upadacitinib is a potent and selective Janus kinase (JAK) 1 inhibitor with an IC50 of 43 nM.

Substance Class	Chemical
Record UNII	4RA0KN46E0
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

UPADACITINIB

Official Name

English

upadacitinib [INN]

Preferred Name

English

ABBV-599 COMPONENT UPADACITINIB

Common Name

English

UPADACITINIB [ORANGE BOOK]

Common Name

English

(3S,4R)-3-ETHYL-4-(3H-IMIDAZO(1,2-A)PYRROLO(2,3-E)PYRAZIN- 8-YL)-N-(2,2,2-TRIFLUOROETHYL)PYRROLIDINE-1-CARBOXAMIDE TYROSINE KINASE INHIBITOR

Common Name

English

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Classification Tree

Code System

Code

Protein Kinase Inhibitor

NCI_THESAURUS

C1967

Designated

FDA ORPHAN DRUG

522916

Designated

FDA ORPHAN DRUG

524116

Designated

FDA ORPHAN DRUG

575517

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Code System

Code

Type

Description

USAN

CD-19

PRIMARY

RXCUI

2196092

PRIMARY

INN

10209

PRIMARY

WIKIPEDIA

Upadacitinib

PRIMARY

SMS_ID

100000173002

PRIMARY

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Related Record

Type

Details


					GL209F9TZS

TYROSINE-PROTEIN KINASE JAK2

TARGETF->WEAK INHIBITOR

Qualification:

IC50

Amount:

200 NANOMOLAR (average)


					08S4A2S6FT

TYROSINE-PROTEIN KINASE JAK1

TARGET -> INHIBITOR


					76UB6O122H

ATP-BINDING CASSETTE SUB-FAMILY G MEMBER 2

TRANSPORTER -> SUBSTRATE


					PUO0521HZV

CYTOCHROME P450 3A4

METABOLIC ENZYME -> SUBSTRATE

Interaction Type:

MAJOR

Amount:


					V094BEF0W8

NON-RECEPTOR TYROSINE-PROTEIN KINASE TYK2

OFF TARGET->WEAK INHIBITOR

Qualification:

IC50

Amount:

4.7 MICROMOLAR (average)

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Related Record

Type

Details


					FVX82Q3ZNW

5-((3R,4S)-4-ETHYL-1-(2,2,2-TRIFLUOROETHYLCARBAMOYL)PYRROLIDIN-3-YL)-1H-IMIDAZOLE-2-CARBOXAMIDE

METABOLITE INACTIVE -> PARENT

Qualification:

URINE

Amount:

0.1 % (average)
of the total radioactive dose


					7AM4F4K5VA

(3S,4R)-3-ETHYL-4-(3H-IMIDAZO(1,2-A)PYRROLO(2,3-E)PYRAZIN-8-YL)-N-(2,2,2-TRIFLUORO-1-HYDROXYETHYL)PYRROLIDINE-1-CARBOXAMIDE

METABOLITE -> PARENT

Interaction Type:

TRACE

Qualification:

FECAL; URINE


					FVX82Q3ZNW

5-((3R,4S)-4-ETHYL-1-(2,2,2-TRIFLUOROETHYLCARBAMOYL)PYRROLIDIN-3-YL)-1H-IMIDAZOLE-2-CARBOXAMIDE

METABOLITE INACTIVE -> PARENT

Qualification:

FECAL

Amount:

6.3 % (average)
of the total radioactive dose


					FVX82Q3ZNW

5-((3R,4S)-4-ETHYL-1-(2,2,2-TRIFLUOROETHYLCARBAMOYL)PYRROLIDIN-3-YL)-1H-IMIDAZOLE-2-CARBOXAMIDE

METABOLITE INACTIVE -> PARENT

Qualification:

PLASMA

Amount:

7.1 % (average)
of the total plasma radioactivity

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Type

Details


					SB92A73Z74

1-(Phenylmethyl) 4-ethyl-2,5-dihydro-1H-pyrrole-1,3-dicarboxylate

IMPURITY -> PARENT

Amount:

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Related Record

Type

Details


					4RA0KN46E0

UPADACITINIB

ACTIVE MOIETY

Amount:

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Name	Property Type	Amount	Parameters
Volume of Distribution	PHARMACOKINETIC	224 LITERS (average)	STEADY-STATE

blood to plasma ratio	PHARMACOKINETIC	1 (average)

Tmax	PHARMACOKINETIC	[2 to 3] hours (average)	FASTED CONDITION ORAL ADMINISTRATION

Biological Half-life	PHARMACOKINETIC	[8 to 14] hours (average)	FOLLOWING THE ADMINISTRATION OF ER FORMULATION

Tmax	PHARMACOKINETIC	6 hours [1.5 to 10] (average)	ORAL ADMINISTRATION FED CONDITION

SMILES

InChI

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