FEDRATINIB

Details

Stereochemistry	ACHIRAL
Molecular Formula	C27H36N6O3S
Molecular Weight	524.678
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

CC1=CN=C(NC2=CC=C(OCCN3CCCC3)C=C2)N=C1NC4=CC=CC(=C4)S(=O)(=O)NC(C)(C)C

InChI

InChIKey=JOOXLOJCABQBSG-UHFFFAOYSA-N

InChI=1S/C27H36N6O3S/c1-20-19-28-26(30-21-10-12-23(13-11-21)36-17-16-33-14-5-6-15-33)31-25(20)29-22-8-7-9-24(18-22)37(34,35)32-27(2,3)4/h7-13,18-19,32H,5-6,14-17H2,1-4H3,(H2,28,29,30,31)

HIDE SMILES / InChI

Molecular Formula	C27H36N6O3S
Molecular Weight	524.678
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

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

Description

Fedratinib (SAR-302503, TG-101348) is a selective small-molecule inhibitor of Janus kinase-2. Fedratinib demonstrated therapeutic efficacy in a murine model of myeloproliferative disease. Sanofi was developing Fedratinib for the treatment of myeloproliferative diseases and solid tumors. The clinical development of fedratinib was terminated after reports of Wernicke's encephalopathy in myelofibrosis patients.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Tyrosine-protein kinase JAK2 55	Inhibitor 8,297		3.0 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Polycythemia vera 15	Primary	Phase II 1,132	Unknown
Myelofibrosis 15	Primary	Phase II 1,132	Unknown
Solid tumors 145	Primary	Phase I 428	Unknown

C_max

Value	Dose	Analyte	Population
1804 ng/mL	400 mg 1 times / day steady-state, oral	FEDRATINIB unknown	Homo sapiens
2539 ng/mL	500 mg 1 times / day steady-state, oral	FEDRATINIB unknown	Homo sapiens
1760 ng/mL	680 mg single, oral	FEDRATINIB plasma	Homo sapiens

AUC

Value	Dose	Analyte	Population
26870 ng × h/mL	400 mg 1 times / day steady-state, oral	FEDRATINIB unknown	Homo sapiens
38712 ng × h/mL	500 mg 1 times / day steady-state, oral	FEDRATINIB unknown	Homo sapiens
17800 ng × h/mL	680 mg single, oral	FEDRATINIB plasma	Homo sapiens

T_1/2

Value	Dose	Co-administered	Analyte	Population
41 h	400 mg 1 times / day steady-state, oral		FEDRATINIB unknown	Homo sapiens
62.1 h	680 mg single, oral		FEDRATINIB plasma	Homo sapiens

F_unbound

Value	Dose	Analyte	Population
8%	400 mg 1 times / day steady-state, oral	FEDRATINIB unknown	Homo sapiens
2%	500 mg 1 times / day steady-state, oral	FEDRATINIB unknown	Homo sapiens
8%		FEDRATINIB plasma	Homo sapiens

Doses

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Dose	Population	Adverse events
400 mg 1 times / day steady, oral Recommended	unhealthy, 27 - 86 years n = 96	Disc. AE: Nausea, Cardiac failure... Other AEs: Diarrhea, Nausea...
400 mg 1 times / day steady, oral Recommended	unhealthy, 27 - 86 years n = 96	Other AEs: Diarrhea, Nausea...
400 mg 1 times / day steady, oral Recommended	unhealthy, 27 - 86 years n = 96	Other AEs: Anemia, Vomiting...
500 mg 1 times / day multiple, oral Studied dose	unhealthy, 65 - 75 years n = 97	Disc. AE: Anemia...
500 mg 1 times / day multiple, oral Studied dose	unhealthy, 65 - 75 years n = 97	Disc. AE: Cardiac disorders...

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AEs

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AE	Significance	Dose	Population
Thrombocytopenia	2%	400 mg 1 times / day steady, oral Recommended	unhealthy, 27 - 86 years n = 96
Blood creatinine increased	2% Disc. AE	400 mg 1 times / day steady, oral Recommended	unhealthy, 27 - 86 years n = 96
Diarrhea	2% Disc. AE	400 mg 1 times / day steady, oral Recommended	unhealthy, 27 - 86 years n = 96
Myocardial ischemia	2% Disc. AE	400 mg 1 times / day steady, oral Recommended	unhealthy, 27 - 86 years n = 96
Thrombocytopenia	2% Disc. AE	400 mg 1 times / day steady, oral Recommended	unhealthy, 27 - 86 years n = 96

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1,737 inhibitor 1,587	inhibitor 1,767	inhibitor 1,852	inhibitor 1,612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
P-gp 1,461 BCRP 699 MATE1 306 MATE2 263 OCT2 647 OATP1B1 788 OATP1B3 706 OAT1 599 OAT3 642 OCT1 512 CYP2C19 1,478 CYP1A2 1,524 CYP2B6 810 CYP2C8 911	P-gp 1,537 CYP2C19 991 FMO3 67 BCRP 561 OATP1B1 406 OATP1B3 350 BSEP 52 MRP2 205	CYP3A 129

Drug as perpetrator

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Target	Modality	Activity
CYP1A2 1,692	inhibitor 3,277	no
CYP2B6 1,001	inhibitor 3,277	no
CYP3A 298	inducer 1,573	no
OAT1 603	inhibitor 3,277	no
OAT3 644	inhibitor 3,277	no

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Drug as victim

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Target	Modality	Activity	Clinical evidence
CYP2C19 991	substrate 3,367	major
FMO3 67	substrate 3,367	major
CYP3A4 1,737	substrate 3,367	major	yes (co-administration study)
BCRP 561	substrate 3,367	no
BSEP 52	substrate 3,367	no

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Tox targets

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Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1,647	inhibitor 1,626

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Sourcing

Sourcing

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Vendor/Aggregator	ID	URL
001 Chemical	DY443054	https://www.001chemical.com/chem/936091-26-8
AA Blocks	AA00GU48	https://www.aablocks.com/goods/Goods/detail?id=AA00GU48
AK Scientific, Inc. (AKSCI)	SYN1104	http://www.aksci.com/item_detail.php?cat=SYN1104
AK Scientific, Inc. (AKSCI)	Y0268	http://www.aksci.com/item_detail.php?cat=Y0268
Aaron Chemicals	AR00GUW0	http://www.aaronchem.com/936091-26-8

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PubMed

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Title	Date	PubMed
Flavanoids induce expression of the suppressor of cytokine signalling 3 (SOCS3) gene and suppress IL-6-activated signal transducer and activator of transcription 3 (STAT3) activation in vascular endothelial cells.	2013 Sep 1	23782265

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Patents

Sample Use Guides

In Vivo Use Guide

Fedratinib therapy in patients with primary or secondary (post-polycythemia vera or post-essential thrombocythemia) MF: once-daily oral fedratinib, at a dose of 400 mg or 500 mg, or placebo, for at least 6 consecutive 4-week cycles. Fedratinib therapy significantly reduced splenomegaly and symptom burden in patients with MF. These benefits were accompanied by toxic effects in some patients, the most important being encephalopathy of unknown mechanism. Clinical development of fedratinib was subsequently discontinued.

Route of Administration: Oral

In Vitro Use Guide

300 nM Fedratinib (SAR-302503, TG-101348) significantly inhibited JAK2V617F+ progenitor-derived colony formation

Substance Class	Chemical
Record UNII	6L1XP550I6
Record Status	`Validated (UNII)`
Record Version

Show entries

Name

Type

Language

FEDRATINIB

Official Name

English

fedratinib [INN]

Common Name

English

BENZENESULFONAMIDE, N-(1,1-DIMETHYLETHYL)-3-((5-METHYL-2-((4-(2-(1-PYRROLIDINYL)ETHOXY)PHENYL)AMINO)-4-PYRIMIDINYL)AMINO)-

Systematic Name

English

FEDRATINIB [MI]

Common Name

English

Fedratinib [WHO-DD]

Common Name

English

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Classification Tree

Code System

Code

Antineoplastic Protein Inhibitor

NCI_THESAURUS

C129825

Tyrosine Kinase Inhibitor

NCI_THESAURUS

C125450

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Code System

Code

Type

Description

DAILYMED

6L1XP550I6

PRIMARY

WIKIPEDIA

TG101348

PRIMARY

FDA UNII

6L1XP550I6

PRIMARY

MERCK INDEX

m12160

PRIMARY

USAN

AB-104

PRIMARY

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Related Record

Type

Details


					6L1XP550I6

FEDRATINIB

EXCRETED UNCHANGED

Interaction Type:

AMOUNT EXCRETED

Qualification:

FECAL

Amount:

22 % (average)
of total dose


					081I12ZA58

CYTOCHROME P450 2C19

METABOLIC ENZYME -> SUBSTRATE

Comments:

Metabolized by CYP3A4 (0 to 70%), CYP2C19 (0‐20%), and FMO3 (0‐33%) in vitro.

Amount:

[<20] % (average)


					4796L35A70

RECEPTOR-TYPE TYROSINE-PROTEIN KINASE FLT3

TARGET -> INHIBITOR

Interaction Type:

INHIBITOR

Qualification:

IC50

Amount:

in-vitro 25 NANOMOLAR (average)


					6D53G0FD0Z

PLASMA PROTEIN FRACTION (HUMAN)

BINDER->LIGAND

Interaction Type:

BINDING

Amount:

[92 to 98] % (average)


					6L1XP550I6

FEDRATINIB

EXCRETED UNCHANGED

Interaction Type:

AMOUNT EXCRETED

Qualification:

URINE

Amount:

3 % (average)
of total dose

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Related Record

Type

Details


					P2P62Q85QH

FEDRATINIB metabolite SAR318031

METABOLITE -> PARENT

Amount:


					HXM94Z3QTY

FEDRATINIB metabolite SAR-317981

METABOLITE LESS ACTIVE -> PARENT

Comments:

2 fold less active than parent. accounting for ~ 9% of the radioactivity AUC.

Interaction Type:

MAJOR

Qualification:

PLASMA

Amount:

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Related Record

Type

Details


					6L1XP550I6

FEDRATINIB

ACTIVE MOIETY

Amount:

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Name	Property Type	Amount	Parameters
Biological Half-life	PHARMACOKINETIC	114 hours (average)

Volume of Distribution	PHARMACOKINETIC	1770 LITERS (average)

Blood to Plasma Ratio	PHARMACOKINETIC	[0.62 to 0.75] (average)

Tmax	PHARMACOKINETIC	3 hours [2 to 4] (average)	STEADY-STATE ONCE DAILY DOSE 400 mg (average) ORAL ADMINISTRATION

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