UPADACITINIB HEMIHYDRATE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	2C17H19F3N6O.H2O
Molecular Weight	778.7504
Optical Activity	UNSPECIFIED
Defined Stereocenters	4 / 4
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

O.CC[C@@H]1CN(C[C@@H]1C2=CN=C3C=NC4=C(C=CN4)N23)C(=O)NCC(F)(F)F.CC[C@@H]5CN(C[C@@H]5C6=CN=C7C=NC8=C(C=CN8)N67)C(=O)NCC(F)(F)F

InChI

InChIKey=GJMQTRCDSIQEFK-SCDRJROZSA-N

InChI=1S/2C17H19F3N6O.H2O/c2*1-2-10-7-25(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;/h2*3-6,10-11,21H,2,7-9H2,1H3,(H,24,27);1H2/t2*10-,11+;/m11./s1

HIDE SMILES / InChI

Molecular Formula	C17H19F3N6O
Molecular Weight	380.3676
Charge	0
Count

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

Molecular Formula	H2O
Molecular Weight	18.0153
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Description
Sources: https://www.abbvie.com/our-science/pipeline/upadacitinib.html | https://ankylosingspondylitisnews.com/upadacitinib-abt-494/ | https://www.ncbi.nlm.nih.gov/pubmed/29076110 | https://www.ncbi.nlm.nih.gov/pubmed/27577235

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 38 Target ID: CHEMBL2835 Sources: https://www.ncbi.nlm.nih.gov/pubmed/27577235	Inhibitor 8297		43.0 nM [IC50]
Tyrosine-protein kinase JAK2 55 Target ID: CHEMBL2971 Sources: https://www.ncbi.nlm.nih.gov/pubmed/27577235	Inhibitor 8297		200.0 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Rheumatoid arthritis 316 Sources: https://www.abbvie.com/our-science/pipeline/upadacitinib.html https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211675s000lbl.pdf https://www.ncbi.nlm.nih.gov/pubmed/31130260	Primary		Approved 8429	RINVOQ Approved Use RINVOQ is a Janus kinase (JAK) inhibitor indicated for the treatment of adults with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate. Launch Date 2019

C_max

Value	Dose	Co-administered	Analyte	Population
63.7 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/29688617	30 mg single, oral dose: 30 mg route of administration: Oral experiment type: SINGLE co-administered:		UPADACITINIB plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

AUC

Value	Dose	Co-administered	Analyte	Population
491 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/29688617	30 mg single, oral dose: 30 mg route of administration: Oral experiment type: SINGLE co-administered:		UPADACITINIB plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

T_1/2

Value	Dose	Co-administered	Analyte	Population
18.1 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/29688617	30 mg single, oral dose: 30 mg route of administration: Oral experiment type: SINGLE co-administered:		UPADACITINIB plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

F_unbound

Value	Dose	Co-administered	Analyte	Population
48% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211675s000lbl.pdf			UPADACITINIB plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
30 mg 1 times / day steady, oral Highest studied dose Dose: 30 mg, 1 times / day Route: oral Route: steady Dose: 30 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/31786154	unhealthy, 39.9 years (range: 18-75 years) n = 42 Health Status: unhealthy Condition: Moderate-to-Severe Atopic Dermatitis Age Group: 39.9 years (range: 18-75 years) Sex: M+F Population Size: 42 Sources: https://pubmed.ncbi.nlm.nih.gov/31786154	Other AEs: Anemia, Neutropenia... Other AEs: Anemia (2.4%) Neutropenia (4.8%) Atopic dermatitis (9.5%) Acne (14%) Headache (9.5%) Nasopharyngitis (7.1%) CPK increased (9.5%) Nausea (7.1%) Sources: https://pubmed.ncbi.nlm.nih.gov/31786154
15 mg 1 times / day steady, oral Recommended Dose: 15 mg, 1 times / day Route: oral Route: steady Dose: 15 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211675s000lbl.pdf	unhealthy, adult Health Status: unhealthy Condition: serious infection Age Group: adult Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211675s000lbl.pdf	Other AEs: Adverse event... Other AEs: Adverse event (grade 5) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211675s000lbl.pdf
15 mg 1 times / day steady, oral Recommended Dose: 15 mg, 1 times / day Route: oral Route: steady Dose: 15 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211675Orig1s000MedR.pdf Page: p. 165	unhealthy, adult n = 1035 Health Status: unhealthy Condition: rheumatoid arthritis Age Group: adult Population Size: 1035 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211675Orig1s000MedR.pdf Page: p. 165	Disc. AE: Anemia, Vertigo... AEs leading to discontinuation/dose reduction: Anemia (2 patients) Vertigo (2 patients) Bronchitis (2 patients) ALT increased (2 patients) Aspartate aminotransferase increased (3 patients) Increased serum creatinine (2 patients) Headache (2 patients) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211675Orig1s000MedR.pdf Page: p. 165

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737 inhibitor 1587	inhibitor 1767	substrate 1217 inhibitor 1852	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 1524 CYP2B6 810 CYP2C19 1478 P-gp 1461 BCRP 699 BSEP 402 OATP1B1 788 OATP1B3 706 OCT1 512 OCT2 647 OAT1 599 OAT3 642 MATE1 306 MATE2 263	CYP3A5 395 P-gp 1537 BCRP 561 OATP1B1 406 OATP1B3 350 OCT1 327	CYP1A2 701 CYP2B6 547 CYP3A 129

Drug as perpetrator

Target	Modality	Activity	Clinical evidence
CYP1A2 1692	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211675Orig1s000ClinPharmR.pdf#page=18 Page: 17, 23	minor
CYP3A4 1925	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211675Orig1s000ClinPharmR.pdf#page=20 Page: 11, 18, 19, 23, 77-85	no [IC50 181 uM]	weak (co-administration study) Comment: Clinically no meaningful effect on midazolam (sensitive CYP3A4 substrate), Coadministration of Upadacitinib (30 mg QD extended-release) decreased Cmax by 16% and AUCinf by 26%., IC50=181 mcM (midazolam) and 212 mcM (teststerone), Upadacitinib caused no detectable time-dependent inhibition of any isoform tested upto a concentration of 50 µM. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211675Orig1s000ClinPharmR.pdf#page=20 Page: 11, 18, 19, 23, 77-85
CYP2C9 1819	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211675Orig1s000ClinPharmR.pdf#page=20 Page: 11, 18, 19, 23, 77-85	no [IC50 40.3 uM]	no (co-administration study) Comment: Clinically no meaningful effect on S-warffarin (sensitive CYP2C9 substrate), Coadministration of Upadacitinib (30 mg QD extended-release) increased Cmax by 7% and AUCinf by 11%., Upadacitinib caused no detectable time-dependent inhibition of any isoform tested up to a concentration of 50 µM. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211675Orig1s000ClinPharmR.pdf#page=20 Page: 11, 18, 19, 23, 77-85
CYP2C19 1553	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211675Orig1s000ClinPharmR.pdf#page=20 Page: 11, 18, 19, 23, 77-85	no [IC50 >250 uM]	no (co-administration study) Comment: Clinically no meaningful effect on omeprazole (sensitive CYP2C19 substrate), Coadministration of Upadacitinib (30 mg QD extended-release) increased AUCinf Ratio (5-OH OME to OME metabolic ratio) by 9%., Upadacitinib caused no detectable time-dependent inhibition of any isoform tested up to a concentration of 50 µM. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211675Orig1s000ClinPharmR.pdf#page=20 Page: 11, 18, 19, 23, 77-85
CYP2D6 1891	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211675Orig1s000ClinPharmR.pdf#page=20 Page: 11, 18, 19, 23, 77-85	no [IC50 >250 uM]	no (co-administration study) Comment: Clinically no meaningful effect on dextromethorphan (sensitive CYP2D6 substrate), Coadministration of Upadacitinib (30 mg QD extended-release) increased Cmax by 9% and AUCinf by 7%., Upadacitinib caused no detectable time-dependent inhibition of any isoform tested up to a concentration of 50 µM. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211675Orig1s000ClinPharmR.pdf#page=20 Page: 11, 18, 19, 23, 77-85
CYP1A2 1692	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211675Orig1s000ClinPharmR.pdf#page=20 Page: 11, 18, 19, 23, 77-85	no [IC50 >250 uM]	weak (co-administration study) Comment: Clinically no meaningful effect on caffeine (sensitive CYP1A2 substrate), Coadministration of Upadacitinib (30 mg QD extended-release) increased Cmax by 13% and AUCinf by 22%., Upadacitinib caused no detectable time-dependent inhibition of any isoform tested up to a concentration of 50 µM. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211675Orig1s000ClinPharmR.pdf#page=20 Page: 11, 18, 19, 23, 77-85
CYP2B6 1001	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211675Orig1s000ClinPharmR.pdf#page=20 Page: 11, 18, 19, 23, 87-89	no [IC50 >250 uM]	weak (co-administration study) Comment: Clinically no meaningful effect on bupropion (CYP2B6 substrate), Coadministration of Upadacitinib (30 mg QD extended-release) decreased Cmax by 13.2% and AUCinf by 7.6%., Upadacitinib caused no detectable time-dependent inhibition of any isoform tested up to a concentration of 50 µM. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211675Orig1s000ClinPharmR.pdf#page=20 Page: 11, 18, 19, 23, 87-89
MATE1 308	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211675Orig1s000ClinPharmR.pdf#page=24 Page: 23.0	unlikely [IC50 10 uM]
MATE2 263	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211675Orig1s000ClinPharmR.pdf#page=24 Page: 23.0	unlikely [IC50 10 uM]
BCRP 773	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211675Orig1s000ClinPharmR.pdf#page=18 Page: 17, 23	unlikely [IC50 120 uM]
BSEP 403	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211675Orig1s000ClinPharmR.pdf#page=24 Page: 23.0	unlikely [IC50 220 uM]
OAT3 644	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211675Orig1s000ClinPharmR.pdf#page=24 Page: 23.0	unlikely [IC50 35 uM]
OATP1B1 803	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211675Orig1s000ClinPharmR.pdf#page=18 Page: 17, 23	unlikely [IC50 48 uM]
P-gp 1650	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211675Orig1s000ClinPharmR.pdf#page=18 Page: 17, 23	unlikely [IC50 510 uM]
OAT1 603	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211675Orig1s000ClinPharmR.pdf#page=24 Page: 23.0	unlikely [IC50 >30 uM]
OATP1B3 715	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211675Orig1s000ClinPharmR.pdf#page=24 Page: 23.0	unlikely [IC50 >30 uM]
OCT1 543	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211675Orig1s000ClinPharmR.pdf#page=24 Page: 23.0	unlikely [IC50 >30 uM]
OCT2 648	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211675Orig1s000ClinPharmR.pdf#page=24 Page: 23.0	unlikely [IC50 >30 uM]
CYP2B6 1001	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211675Orig1s000ClinPharmR.pdf#page=18 Page: 17, 23	yes
CYP3A 298	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211675Orig1s000ClinPharmR.pdf#page=18 Page: 17, 23	yes

Drug as victim

Target	Modality	Activity	Clinical evidence
CYP3A4 1737	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211675Orig1s000ClinPharmR.pdf#page=6 Page: 5, 10, 17, 18, 23, 70-72	major	yes (co-administration study) Comment: When upadacitinib was co-administered with ketoconazole (a strong CYP3A4 inhibitor, 400 mg QD x 6 days), upadacitinib exposure increased by 75% for AUC0-inf and 70% for Cmax. Upadacitinib should be used with caution if patients receive chronic treatment with strong CYP3A4 inhibitors. When upadacitinib was co-administered with rifampin (a strong CYP3A4 inducer, 600 mg QD x 9 days), upadacitinib exposure decreased by 61% for AUC0-inf and 51% for Cmax. Upadacitinib is not recommended to be co-administered with strong CYP3A4 inducers. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211675Orig1s000ClinPharmR.pdf#page=6 Page: 5, 10, 17, 18, 23, 70-72
CYP2D6 1217	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211675Orig1s000ClinPharmR.pdf#page=6 Page: 5, 11, 17	minor
CYP3A5 395	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211675Orig1s000ClinPharmR.pdf#page=23; https://www.pmda.go.jp/drugs/2020/P20200120001/112130000_30200AMX00028_I101_2.pdf#page=18 Page: 22-23, (PMD) 18	minor
OATP1B3 350	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211675Orig1s000ClinPharmR.pdf#page=24 Page: 23.0	no
OCT1 327	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211675Orig1s000ClinPharmR.pdf#page=24 Page: 23.0	no
OATP1B1 406	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211675Orig1s000ClinPharmR.pdf#page=12 Page: 11, 18, 23	no	no (co-administration study) Comment: OATP1B inhibitor (rifampin, 600 mg SD) do not have clinically meaningful effect on upadacitinib PK (increased Cmax by 14% and AUCinf by 7%). Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211675Orig1s000ClinPharmR.pdf#page=12 Page: 11, 18, 23
BCRP 561	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211675Orig1s000ClinPharmR.pdf#page=11 Page: 10, 17, 23	yes
P-gp 1537	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211675Orig1s000ClinPharmR.pdf#page=11 Page: 10, 17, 23	yes

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211675Orig1s000PharmR.pdf#page=49 Page: 20.0

Sourcing

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
Achemtek	0102-032615	http://achemtek.com/1310726-60-3-2
Acorn PharmaTech	ACN-052823	http://www.acornpharmatech.com/
Ambeed	A165008	https://www.ambeed.com/products/1310726-60-3.html
BioChemPartner	BCP19011	http://www.biochempartner.com/1310726-60-3-BCP19011
CSNpharm	CSN18721	https://www.csnpharm.com/products/upadacitinib.html
Chem Scene	CS-6150	http://www.chemscene.com/1310726-60-3.html
ChemFish Tokyo co.,ltd	58557659	http://www.chemfish.co.jp/index.php?id=2929&project=product
Chemspace	CSSB00103150878	https://chem-space.com/CSSB00103150878
DC Chemicals	DC10431	http://www.dcchemicals.com/product_show-Upadacitinib.html
Excenen	EX-A1628	http://www.excenen.com/searchresultlist.php?id=1310726-60-3
Hairui	UPXF018	http://www.hairuichem.com/en/product/1310726-60-3.html
Lab Network	LN03250514	https://labnetwork.com/frontend-app/p/#!/moleculedetails/LN03250514
MedChem Express	HY-19569	https://www.medchemexpress.com/Upadacitinib.html
Selleck Chemicals	S8162	http://www.selleckchem.com/products/upadacitinib.html
Smolecule	S546407	http://www.smolecule.com/products/s546407
Synblock Inc	SB19218	http://www.synblock.com/product/1310726-60-3.html
THE BioTek	bt-285013	https://www.thebiotek.com/product/inhibitors/bt-285013
abcr GmbH	AB514878	http://www.abcr.com/shop/en/AB514878
eNovation Chemicals	Y0975799	https://www.enovationchem.com/ProductDetails.asp?ProductID=Y0975799
iChemical	EBD4040026	http://www.ichemical.com/products/1310726-60-3.html?utm_source=PubChem&utm_medium=website&utm_campaign=product%20catalogs

PubMed

Title	Date	PubMed
Pharmacokinetics, Safety and Tolerability of ABT-494, a Novel Selective JAK 1 Inhibitor, in Healthy Volunteers and Subjects with Rheumatoid Arthritis.	2016 Dec	27272171

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 Created by `admin` on `Sat Dec 16 14:32:41 GMT 2023` Edited by `admin` on `Sat Dec 16 14:32:41 GMT 2023`
Record UNII	NEW4DV02U5
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

UPADACITINIB HEMIHYDRATE

Common Name

English

Upadacitinib hemihydrate [WHO-DD]

Common Name

English

1-PYRROLIDINECARBOXAMIDE, 3-ETHYL-4-(3H-IMIDAZO(1,2-A)PYRROLO(2,3-E)PYRAZIN-8-YL)-N-(2,2,2-TRIFLUOROETHYL)-, HYDRATE (2:1), (3S,4R)-

Common Name

English

UPADACITINIB HYDRATE [JAN]

Common Name

English

RINVOQ

Brand Name

English

Code System Code Type Description

FDA UNII

NEW4DV02U5