TAMATINIB

Details

Stereochemistry	ACHIRAL
Molecular Formula	C22H23FN6O5
Molecular Weight	470.4536
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

COC1=CC(NC2=NC=C(F)C(NC3=CC=C4OC(C)(C)C(=O)NC4=N3)=N2)=CC(OC)=C1OC

InChI

InChIKey=NHHQJBCNYHBUSI-UHFFFAOYSA-N

InChI=1S/C22H23FN6O5/c1-22(2)20(30)28-19-13(34-22)6-7-16(27-19)26-18-12(23)10-24-21(29-18)25-11-8-14(31-3)17(33-5)15(9-11)32-4/h6-10H,1-5H3,(H3,24,25,26,27,28,29,30)

HIDE SMILES / InChI

Description

R406 (TAMATINIB) is an ATP-competitive inhibitor of spleen tyrosine kinase (Syk), which plays a key role in the signaling of activating Fc receptors and the B-cell receptor (BCR). R406 blocked Syk-dependent FcR-mediated activation of monocytes/macrophages and neutrophils and BCR-mediated activation of B lymphocytes. R406 was selective as assessed using a large panel of Syk-independent cell-based assays representing both specific and general signaling pathways. Consistent with Syk inhibition, oral administration of R406 to mice reduced immune complex-mediated inflammation in a reverse-passive Arthus reaction and two antibody-induced arthritis models. R406 is the active compound of pro-drug Fostamatinib (R-788). Fostamatinib is being developed by Rigel Pharmaceuticals for the treatment of immune thrombocytopenic purpura (ITP) and IgA nephropathy.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Tyrosine-protein kinase SYK 21	Inhibitor 8,297		30.0 nM [Ki]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Immune thrombocytopenia 9	Primary		Phase III 656	Unknown
IgA nephropathy 4	Primary		Phase II 1,132	Unknown

C_max

Value	Dose	Analyte	Population
501 ng/mL	80 mg single, oral	R406 plasma	Homo sapiens
2030 ng/mL	250 mg single, oral	R406 plasma	Homo sapiens
3410 ng/mL	400 mg single, oral	R406 plasma	Homo sapiens
3660 ng/mL	500 mg single, oral	R406 plasma	Homo sapiens
3920 ng/mL	600 mg single, oral	R406 plasma	Homo sapiens
306 ng/mL	80 mg single, oral	R406 plasma	Homo sapiens
1140 ng/mL	250 mg single, oral	R406 plasma	Homo sapiens
1220 ng/mL	400 mg single, oral	R406 plasma	Homo sapiens
682 ng/mL	100 mg single, oral	R406 plasma	Homo sapiens
605 ng/mL	75 mg single, oral	R406 plasma	Homo sapiens
363 ng/mL	75 mg single, oral	R406 plasma	Homo sapiens
747 ng/mL	160 mg 2 times / day multiple, oral	R406 plasma	Homo sapiens
1530 ng/mL	160 mg 2 times / day steady-state, oral	R406 plasma	Homo sapiens
397 ng/mL	100 mg 2 times / day multiple, oral	R406 plasma	Homo sapiens
761 ng/mL	100 mg 2 times / day steady-state, oral	R406 plasma	Homo sapiens
690 ng/mL	150 mg single, oral	R406 plasma	Homo sapiens
425 ng/mL	150 mg single, oral	R406 plasma	Homo sapiens
407 ng/mL	150 mg single, oral	R406 plasma	Homo sapiens
529 ng/mL	150 mg single, oral	R406 plasma	Homo sapiens
692 ng/mL	150 mg single, oral	R406 plasma	Homo sapiens
615 ng/mL	150 mg single, oral	R406 plasma	Homo sapiens
602 ng/mL	150 mg single, oral	R406 plasma	Homo sapiens
582 ng/mL	150 mg single, oral	R406 plasma	Homo sapiens

AUC

Value	Dose	Analyte	Population
4410 ng × h/mL	80 mg single, oral	R406 plasma	Homo sapiens
18100 ng × h/mL	250 mg single, oral	R406 plasma	Homo sapiens
34900 ng × h/mL	400 mg single, oral	R406 plasma	Homo sapiens
29600 ng × h/mL	500 mg single, oral	R406 plasma	Homo sapiens
36600 ng × h/mL	600 mg single, oral	R406 plasma	Homo sapiens
3150 ng × h/mL	80 mg single, oral	R406 plasma	Homo sapiens
13700 ng × h/mL	250 mg single, oral	R406 plasma	Homo sapiens
13400 ng × h/mL	400 mg single, oral	R406 plasma	Homo sapiens
7510 ng × h/mL	100 mg single, oral	R406 plasma	Homo sapiens
6490 ng × h/mL	75 mg single, oral	R406 plasma	Homo sapiens
7140 ng × h/mL	75 mg single, oral	R406 plasma	Homo sapiens
8250 ng × h/mL	160 mg 2 times / day multiple, oral	R406 plasma	Homo sapiens
19900 ng × h/mL	160 mg 2 times / day steady-state, oral	R406 plasma	Homo sapiens
3260 ng × h/mL	100 mg 2 times / day multiple, oral	R406 plasma	Homo sapiens
6750 ng × h/mL	150 mg single, oral	R406 plasma	Homo sapiens
6110 ng × h/mL	150 mg single, oral	R406 plasma	Homo sapiens
4950 ng × h/mL	150 mg single, oral	R406 plasma	Homo sapiens
6280 ng × h/mL	150 mg single, oral	R406 plasma	Homo sapiens
8970 ng × h/mL	150 mg single, oral	R406 plasma	Homo sapiens
6390 ng × h/mL	150 mg single, oral	R406 plasma	Homo sapiens
6860 ng × h/mL	150 mg single, oral	R406 plasma	Homo sapiens
9490 ng × h/mL	150 mg single, oral	R406 plasma	Homo sapiens

T_1/2

Value	Dose	Analyte	Population
14.5 h	80 mg single, oral	R406 plasma	Homo sapiens
14.9 h	250 mg single, oral	R406 plasma	Homo sapiens
17.8 h	400 mg single, oral	R406 plasma	Homo sapiens
20.9 h	500 mg single, oral	R406 plasma	Homo sapiens
12.9 h	600 mg single, oral	R406 plasma	Homo sapiens
14.8 h	80 mg single, oral	R406 plasma	Homo sapiens
16 h	250 mg single, oral	R406 plasma	Homo sapiens
12.1 h	400 mg single, oral	R406 plasma	Homo sapiens
19 h	100 mg single, oral	R406 plasma	Homo sapiens
17.9 h	75 mg single, oral	R406 plasma	Homo sapiens
18.4 h	75 mg single, oral	R406 plasma	Homo sapiens
19.9 h	160 mg 2 times / day multiple, oral	R406 plasma	Homo sapiens
14.5 h	100 mg 2 times / day multiple, oral	R406 plasma	Homo sapiens
20.4 h	100 mg 2 times / day steady-state, oral	R406 plasma	Homo sapiens
20.5 h	150 mg single, oral	R406 plasma	Homo sapiens
23.8 h	150 mg single, oral	R406 plasma	Homo sapiens
19.6 h	150 mg single, oral	R406 plasma	Homo sapiens
22.1 h	150 mg single, oral	R406 plasma	Homo sapiens
19.4 h	150 mg single, oral	R406 plasma	Homo sapiens
16.7 h	150 mg single, oral	R406 plasma	Homo sapiens
16.1 h	150 mg single, oral	R406 plasma	Homo sapiens
19.2 h	150 mg single, oral	R406 plasma	Homo sapiens

F_unbound

Value	Dose	Co-administered	Analyte	Population
3.7%	80 mg single, oral		R406 plasma	Homo sapiens

Sourcing

Sourcing

Show entries

Vendor/Aggregator	ID	URL
001 Chemical	DY110886	https://www.001chemical.com/chem/search?q=DY110886
1PlusChem LLC	1P008HDZ	https://www.1pchem.com/search?query=1P008HDZ
1PlusChem LLC	1P00G46D	https://www.1pchem.com/search?query=1P00G46D
AChemBlock	A-624	http://www.achemblock.com/catalogsearch/result/?q=A-624
AK Scientific	SYN1121	https://aksci.com/item_detail.php?cat=SYN1121

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PubMed

Show entries

Title	Date	PubMed
R406, an orally available spleen tyrosine kinase inhibitor blocks fc receptor signaling and reduces immune complex-mediated inflammation.	2006 Dec	16946104
B-cell antigen receptor signaling enhances chronic lymphocytic leukemia cell migration and survival: specific targeting with a novel spleen tyrosine kinase inhibitor, R406.	2009 Jul 30	19491390

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Patents

Sample Use Guides

In Vivo Use Guide

Pharmacokinetic assessment indicated that R406 was highly bioavailable. R406 plasma concentration increased in a dose-proportional fashion up to 400 mg and then reached a plateau. The maximal R406 concentration was generally reached between 1.2 and 1.3 h after dosing, and the half-life was approximately 15 h.

Route of Administration: Oral

In Vitro Use Guide

BCR triggering increases CLL cell viability, and 5 uM R406 abrogates BCR-derived survival signals

Show entries

Name

Type

Language

TAMATINIB

Common Name

English

R940406

Common Name

English

2H-PYRIDO(3,2-B)-1,4-OXAZIN-3(4H)-ONE, 6-((5-FLUORO-2-((3,4,5-TRIMETHOXYPHENYL)AMINO)-4-PYRIMIDINYL)AMINO)-2,2-DIMETHYL-

Systematic Name

English

R-406

Common Name

English

6-(5-FLUORO-2-(3,4,5-TRIMETHOXY-PHENYLAMINO)-PYRIMIDIN-4-YLAMINO)-2,2-DIMETHYL-4H-PYRIDO(3,2-B)(1,4)OXAZIN-3-ONE

Systematic Name

English

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Show entries

Code System

Code

Type

Description

WIKIPEDIA

R-406

PRIMARY

PUBCHEM

11213558

PRIMARY

DRUG BANK

DB07159

PRIMARY

EPA CompTox

DTXSID30458939

PRIMARY

FDA UNII

RC3A285J2G

PRIMARY

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ACTIVE MOIETY


					RC3A285J2G

TAMATINIB

METABOLITE (PARENT)


					B5MW0MGI3L

P-DE(METHOXY)-M,M-DEMETHYL-TAMATINIB

SMILES

InChI

Originator

Approval Year

Targets

Conditions

Cmax

AUC

T1/2

Funbound

Sourcing

PubMed

Patents

Sample Use Guides

C_max

T_1/2

F_unbound