FOSTAMATINIB DISODIUM

Details

Stereochemistry	ACHIRAL
Molecular Formula	C23H24FN6O9P.2Na.6H2O
Molecular Weight	732.5148
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

O.O.O.O.O.O.[Na+].[Na+].COC1=CC(NC2=NC=C(F)C(NC3=NC4=C(OC(C)(C)C(=O)N4COP([O-])([O-])=O)C=C3)=N2)=CC(OC)=C1OC

InChI

InChIKey=ZQGJCHHKJNSPMS-UHFFFAOYSA-L

InChI=1S/C23H26FN6O9P.2Na.6H2O/c1-23(2)21(31)30(11-38-40(32,33)34)20-14(39-23)6-7-17(28-20)27-19-13(24)10-25-22(29-19)26-12-8-15(35-3)18(37-5)16(9-12)36-4;;;;;;;;/h6-10H,11H2,1-5H3,(H2,32,33,34)(H2,25,26,27,28,29);;;6*1H2/q;2*+1;;;;;;/p-2

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Description

Fostamatinib is a pro-drug of a Syk inhibitor R406 initially developed by Rigel Pharmaceuticals, but then in-licensed by AstraZeneca. It reached phase III of clinical trials for such diseases as Rheumatoid Arthritis and Immune Thrombocytopenic Purpura, however, AstraZeneca decided not to proceed with regulatory filings and return the rights to the compound to Rigel Pharmaceuticals. In 2018 the drug was approved by the FDA for treatment of chronic immune thrombocytopenia. Fostamatinib is being developed for Autoimmune Hemolytic Anemia (phase II), graft versus host disease (phase I) and ovarian cancer (phase I).

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Tyrosine-protein kinase SYK 21	Inhibitor 8,297		41.0 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Ovarian cancer 157	Primary	Phase I 428	Unknown
Immune thrombocytopenia 9	Primary	Approved 8,429	Tavalisse
Rheumatoid arthritis 316	Primary	Phase III 656	Unknown
Autoimmune hemolytic anemia 3	Primary	Phase II 1,132	Unknown
IgA nephropathy 4	Primary	Phase II 1,132	Unknown

C_max

Value	Dose	Analyte	Population
1140 ng/mL	250 mg single, oral	R-406 plasma	Homo sapiens
1530 ng/mL	160 mg 2 times / day multiple, oral	R-406 plasma	Homo sapiens
747 ng/mL	160 mg 2 times / day multiple, oral	R-406 plasma	Homo sapiens
605 ng/mL	75 mg single, oral	R406 plasma	Homo sapiens

AUC

Value	Dose	Analyte	Population
13700 ng × h/mL	250 mg single, oral	R-406 plasma	Homo sapiens
19900 ng × h/mL	160 mg 2 times / day multiple, oral	R-406 plasma	Homo sapiens
8250 ng × h/mL	160 mg 2 times / day multiple, oral	R-406 plasma	Homo sapiens
6490 ng × h/mL	75 mg single, oral	R406 plasma	Homo sapiens

T_1/2

Value	Dose	Analyte	Population
16 h	250 mg single, oral	R-406 plasma	Homo sapiens
19.9 h	160 mg 2 times / day multiple, oral	R-406 plasma	Homo sapiens
17.9 h	75 mg single, oral	R406 plasma	Homo sapiens

F_unbound

Value	Dose	Co-administered	Analyte	Population
2%	150 mg 2 times / day multiple, oral		R-406 plasma	Homo sapiens

Doses

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Dose	Population	Adverse events
200 mg 2 times / day multiple, oral Highest studied dose	unhealthy, 34-82 years	Other AEs: Lymphopenia, Hypertension...
260 mg 1 times / day multiple, oral	unhealthy, 53.5 years (range: 20 - 88 years)	Disc. AE: Abdominal pain, ALT increased...

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AEs

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AE	Significance	Dose	Population
Diarrhea	grade 1-2, 14%	200 mg 2 times / day multiple, oral Highest studied dose	unhealthy, 34-82 years
Fatigue	grade 1-2, 14%	200 mg 2 times / day multiple, oral Highest studied dose	unhealthy, 34-82 years
Neutropenia	grade 1-2, 14%	200 mg 2 times / day multiple, oral Highest studied dose	unhealthy, 34-82 years
Anemia	grade 1-2, 29%	200 mg 2 times / day multiple, oral Highest studied dose	unhealthy, 34-82 years
Thrombocytopenia	grade 1-2, 29%	200 mg 2 times / day multiple, oral Highest studied dose	unhealthy, 34-82 years

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Overview

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

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
P-gp 1,461 BCRP 699 UGT1A1 204 UGT2B7 146 CYP2C8 911	BCRP 561 alkaline phosphatase 6 OCT2 355 OATP1B1/3 11 MRP2 205 P-gp 1,537 UGT1A9 380	CYP2C8 168

Drug as perpetrator

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Target	Modality	Activity	Metabolite	Clinical evidence
CYP2C8 965	inhibitor 3,277	no	R406 3
UGT2B7 157	inhibitor 3,277	no	R406 3
UGT1A1 254	inhibitor 3,277	yes	R406 3
CYP2C8 965	inducer 1,573	yes	R406 3	no (co-administration study)
BCRP 773	inhibitor 3,277	yes	R406 3	yes (co-administration study)

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Drug as victim

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Target	Modality	Activity	Metabolite	Clinical evidence
UGT1A9 380	substrate 3,367	major	R406 3
alkaline phosphatase 6	substrate 3,367	major
CYP3A4 1,737	substrate 3,367	major	R406 3	yes (co-administration study)
BCRP 561	substrate 3,367	no	R406 3
MRP2 205	substrate 3,367	no	R406 3

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Tox targets

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Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1,647	inhibitor 1,626		R406 3

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Sourcing

Sourcing

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Vendor/Aggregator	ID	URL
001 Chemical	DY105510	https://www.001chemical.com/chem/901119-35-5
AA Blocks	AA00GU37	https://www.aablocks.com/goods/Goods/detail?id=AA00GU37
Aaron Chemicals	AR00GUUZ	http://www.aaronchem.com/901119-35-5
abcr GmbH	AB457968	http://www.abcr.com/shop/en/AB457968
AbMole Bioscience	M1990	http://www.abmole.com/products/r788.html

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PubMed

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Title	Date	PubMed
R406, an orally available spleen tyrosine kinase inhibitor blocks fc receptor signaling and reduces immune complex-mediated inflammation.	2006 Dec	16946104

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Patents

Sample Use Guides

In Vivo Use Guide

Rheumatoid Arthritis: 100 mg twice daily or 150 mg once daily. Immune Thrombocytopenic Purpura: 100 mg or 150 mg twice daily for 24 weeks. IGA Nephropathy: 100 mg or 150 mg twice daily for 15 months. Autoimmune Hemolytic Anemia: 100 mg or 150 mg twice daily for 12 weeks.

Route of Administration: Oral

In Vitro Use Guide

In primary human B cells, active metabolite of fostamatinib, R406, inhibited CD69 up-regulation in response to anti-IgM with an EC50 of 48 nM. EC50 for IgE-induced degranulation of primary human mast cells in vitro was 56 nM.

Show entries

Name

Type

Language

FOSTAMATINIB DISODIUM

Official Name

English

R935788 SODIUM

Code

English

[6-({5-Fluoro-2-[(3,4,5-trimethoxyphenyl)amino]pyrimidin-4-yl}amino)-2,2-dimethyl-3-oxo-2,3-dihydro-4H-pyrido[3,2-b]-1,4-oxazin-4-yl]methyl disodium phosphate hexahydrate

Common Name

English

TAVALISSE

Brand Name

English

R-935788 SODIUM HYDRATE

Code

English

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Classification Tree

Code System

Code

Protein Kinase Inhibitor

NCI_THESAURUS

C1967

Designated/Approved

FDA ORPHAN DRUG

487715

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Code System

Code

Type

Description

EVMPD

SUB32625

PRIMARY

EVMPD

SUB197641

ALTERNATIVE

NCI_THESAURUS

C69128

PRIMARY

PUBCHEM

24828759

PRIMARY

DRUG BANK

DBSALT002691

PRIMARY

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ACTIVE MOIETY


					SQ8A3S5101

FOSTAMATINIB

SALT/SOLVATE (SALT/SOLVATE)


					X9417132K8

FOSTAMATINIB DISODIUM ANHYDROUS

SUBSTANCE RECORD


					86EEZ49YVB

FOSTAMATINIB DISODIUM

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