FOSTAMATINIB

Details

Stereochemistry	ACHIRAL
Molecular Formula	C23H26FN6O9P
Molecular Weight	580.4595
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

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=GKDRMWXFWHEQQT-UHFFFAOYSA-N

InChI=1S/C23H26FN6O9P/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)

HIDE SMILES / InChI

Description
Sources: https://www.astrazeneca.com/content/dam/az/PDF/Fostamatinib-analyst-briefing.pdf | https://www.ncbi.nlm.nih.gov/pubmed/23284223 | http://www.rigel.com/index.php/pipeline/

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 Target ID: CHEMBL2599 Sources: https://www.astrazeneca.com/content/dam/az/PDF/Fostamatinib-analyst-briefing.pdf	Inhibitor 8297		41.0 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Ovarian cancer 157 Sources: https://clinicaltrials.gov/ct2/show/NCT03246074	Primary	Phase I 428	Unknown Approved Use Unknown
Immune thrombocytopenia 9 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209299lbl.pdf	Primary	Approved 8429	Tavalisse Approved Use TAVALISSE is a kinase inhibitor indicated for the treatment of thrombocytopenia in adult patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment. Launch Date 2018
Rheumatoid arthritis 316 Sources: https://www.ncbi.nlm.nih.gov/pubmed/25225285	Primary	Phase III 656	Unknown Approved Use Unknown
Autoimmune hemolytic anemia 3 Sources: https://clinicaltrials.gov/ct2/show/NCT02612558	Primary	Phase II 1132	Unknown Approved Use Unknown
IgA nephropathy 4 Sources: https://clinicaltrials.gov/ct2/show/NCT02433236	Primary	Phase II 1132	Unknown Approved Use Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
605 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/23190017	75 mg single, oral dose: 75 mg route of administration: Oral experiment type: SINGLE co-administered:		R406 plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

AUC

Value	Dose	Co-administered	Analyte	Population
6490 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/23190017	75 mg single, oral dose: 75 mg route of administration: Oral experiment type: SINGLE co-administered:		R406 plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

T_1/2

Value	Dose	Co-administered	Analyte	Population
17.9 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/23190017	75 mg single, oral dose: 75 mg route of administration: Oral experiment type: SINGLE co-administered:		R406 plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

Doses

Dose	Population	Adverse events
200 mg 2 times / day multiple, oral Highest studied dose Dose: 200 mg, 2 times / day Route: oral Route: multiple Dose: 200 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/23404627	unhealthy, 34-82 years n = 7 Health Status: unhealthy Age Group: 34-82 years Sex: M+F Population Size: 7 Sources: https://pubmed.ncbi.nlm.nih.gov/23404627	Other AEs: Lymphopenia, Hypertension... Other AEs: Lymphopenia (grade 3-5, 14%) Hypertension (grade 3-5, 29%) Aspartate aminotransferase increased (grade 3-5, 14%) Alkaline phosphatase increased (grade 3-5, 29%) Hyperbilirubinemia (grade 3-5, 14%) Anemia (grade 1-2, 29%) Leukopenia (grade 1-2, 57%) Neutropenia (grade 1-2, 14%) Thrombocytopenia (grade 1-2, 29%) Diarrhea (grade 1-2, 14%) Fatigue (grade 1-2, 14%) ALT increased (grade 1-2, 71%) Sources: https://pubmed.ncbi.nlm.nih.gov/23404627
260 mg 1 times / day multiple, oral (median) Dose: 260 mg, 1 times / day Route: oral Route: multiple Dose: 260 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/209299Orig1s000MultidisciplineR.pdf Page: p. 166	unhealthy, 53.5 years (range: 20 - 88 years) n = 102 Health Status: unhealthy Age Group: 53.5 years (range: 20 - 88 years) Sex: M+F Population Size: 102 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/209299Orig1s000MultidisciplineR.pdf Page: p. 166	Disc. AE: Abdominal pain, ALT increased... AEs leading to discontinuation/dose reduction: Abdominal pain (1%) ALT increased (1%) Chest pain (1%) Headache (1%) Neutropenia (1%) Pneumonia (1%) Plasma cell myeloma (1%) Syncope (1%) Thrombocytopenia (1%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/209299Orig1s000MultidisciplineR.pdf Page: p. 166

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737 inhibitor 1587			inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
P-gp 1461 BCRP 699 UGT1A1 204 UGT2B7 146 CYP2C8 911	BCRP 561 alkaline phosphatase 6 OCT2 355 OATP1B1/3 11 MRP2 205 P-gp 1537 UGT1A9 380	CYP2C8 168

Drug as perpetrator

Target	Modality	Activity	Metabolite	Clinical evidence
CYP2C8 965	inhibitor 3277 Sources: https://www.ema.europa.eu/en/documents/product-information/tavlesse-epar-product-information_en.pdf#page=8 Page: (EMA product info) 8	no	R406 3
UGT2B7 157	inhibitor 3277 Sources: https://www.ema.europa.eu/en/documents/product-information/tavlesse-epar-product-information_en.pdf#page=8 Page: (EMA product info) 8	no	R406 3
UGT1A1 254	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/209299Orig1s000MultidisciplineR.pdf#page=69, https://www.ema.europa.eu/en/documents/product-information/tavlesse-epar-product-information_en.pdf#page=9 Page: 68, (EMA product info) 9	yes	R406 3
CYP2C8 965	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/209299Orig1s000MultidisciplineR.pdf#page=79 Page: 68, 78	yes	R406 3	no (co-administration study) Comment: Coadministration of fostamatinib (100 mg BID x 8 days) decreased mean Cmax of pioglitazone and hydroxypioglitazone by 117% and 9%. The mean AUC was increased by 18% and decreased 10% for pioglitazone (AUC(0-inf)) and hydroxypioglitazone (AUC(0-48hr)), respectively. No dose modification of fostamatinib is needed when co-administering with CYP2C8 substrates. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/209299Orig1s000MultidisciplineR.pdf#page=79 Page: 68, 78
BCRP 773	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/209299Orig1s000MultidisciplineR.pdf#page=69 Page: 68, 78-79	yes	R406 3	yes (co-administration study) Comment: Coadministration of fostamatinib (100 mg BID x 9 days) increased mean rosuvastatin (20 mg on Day 6) Cmax by 88% and mean AUC(0-inf) by 96%. Monitor for toxicities that may require dosage reduction of BCRP substrates (such as, rosuvastatin) when co-administering with fostamatinib. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/209299Orig1s000MultidisciplineR.pdf#page=69 Page: 68, 78-79
CYP3A4 1925	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/209299Orig1s000MultidisciplineR.pdf#page=78 Page: 68, 77-78	yes	R406 3	yes (co-administration study) Comment: Coadministration of fostamatinib (100 mg BID x 6 days) increased mean midazolam (7.5 mg on Day 7) Cmax by 9% and mean AUC(0-inf) by 25%. Coadministration of fostamatinib (100 mg BID x 7 days) increased mean Cmax of simvastatin (40mg on Day 6) and simvastatin acid by 113% and 83% and mean AUC(0-inf) by 64% and 66%. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/209299Orig1s000MultidisciplineR.pdf#page=78 Page: 68, 77-78
P-gp 1650	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/209299Orig1s000MultidisciplineR.pdf#page=80 Page: 68, 79	yes		yes (co-administration study) Comment: Coadministration of fostamatinib (100 mg BID on Day 9 to Day 15) increased mean Cmax,ss of digoxin (a loading dose of 0.25 mg BID on Day 1 and 0.25 mg QD on Day 2 to Day 15) by 70% and mean AUCss by 37%. Monitor for toxicities that may require dosage reduction of P-gp substrates (such as, digoxin) when co-administering with fostamatinib. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/209299Orig1s000MultidisciplineR.pdf#page=80 Page: 68, 79

Drug as victim

Target	Modality	Activity	Metabolite	Clinical evidence
UGT1A9 380	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/209299Orig1s000MultidisciplineR.pdf#page=69 Page: 68.0	major	R406 3
alkaline phosphatase 6	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/209299Orig1s000MultidisciplineR.pdf#page=67 Page: 66.0	major
CYP3A4 1737	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/209299Orig1s000MultidisciplineR.pdf#page=76 Page: 64, 68, 75, 76	major	R406 3	yes (co-administration study) Comment: The AUC(0-inf) and Cmax of R406 (Fostamatinib 80mg, 2 hr after the 2nd dose of ketoconazole) was increased by 102% and 37% when fostamatinib was co-administered with ketoconazole (200 mg BID x 7 days, strong CYP3A4 inhibitor). The mean terminal t1/2 increased from 14 hr to 18 hr. Co-administration of verapamil (80 mg TID x 4 days, moderate CYP3A4 inhibitor) increased mean Cmax of R406 (fostamatinib 150 mg on the 2nd day w/verapamil) by 6% and mean AUC(0-inf) by 39%. The mean terminal t1/2 increased from 14 hours to 19 hours. Avoid concomitant use of strong CYP3A inducer due to the concern of loss of efficacy as the mean AUC(0-inf) of R406 (fostamatinib 150 mg on Day 6) was decreased by 75% and Cmax by 59% when fostamatinib was co-administration with rifampicin (600 mg QD x 8 days, strong CYP3A4 inducer). Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/209299Orig1s000MultidisciplineR.pdf#page=76 Page: 64, 68, 75, 76
BCRP 561	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209299lbl.pdf#page=13 Page: 13.0	no	R406 3
MRP2 205	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209299lbl.pdf#page=13 Page: 13.0	no	R406 3
OATP1B1/3 11	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209299lbl.pdf#page=13 Page: 13.0	no	R406 3
OCT2 355	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209299lbl.pdf#page=13 Page: 13.0	no	R406 3
P-gp 1537	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/209299Orig1s000MultidisciplineR.pdf#page=68 Page: 67.0	yes	R406 3

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/209299Orig1s000MultidisciplineR.pdf#page=35 Page: 34.0		R406 3

Sourcing

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
AbMole Bioscience	M1990	http://www.abmole.com/products/r788.html
Aceschem	ACF022912	https://www.aceschem.com/catalog/901119-35-5.html
Achemo Scientific Limited	AC-27492	http://www.achemo.com/product_view.asp?ID=25381
Achemtek	0102-012257	http://www.achemtek.com/901119-35-5
Active Biopharma	ABP000970	http://www.activebiopharma.com/901119-35-5
Adooq BioScience	A11926	https://www.adooq.com/r788-fostamatinib.html
Ambinter	Amb22395933	http://www.ambinter.com/reference/22395933
Angel Pharmatech	AG-12026	http://www.angelpharmatech.com/901119-35-5.html
Angene	AGN-PC-00DTWF	http://www.angenechemical.com/productshow/AGN-PC-00DTWF.html
ApexBio Technology	B2284	http://www.apexbt.com/fostamatinib-r788.html
Ark Pharma Scientific Limited	A-0473	http://www.arkpharmtech.com/product/32424.html
Aurora Fine Chemicals LLC	A24.090.818	http://online.aurorafinechemicals.com/info?ID=A24.090.818
Aurora Fine Chemicals LLC	K16.644.798	http://online.aurorafinechemicals.com/info?ID=K16.644.798
Aurum Pharmatech LLC	Q-4555	http://www.Aurumpharmatech.com/Product/ProductDetails/Q_4555
BOC Sciences	901119-35-5	https://www.bocsci.com/fostamatinib-cas-901119-35-5-item-84-307765.html
BioChemPartner	BCP01871	http://www.biochempartner.com/901119-35-5-BCP01871
BioCrick	BCC5082	http://www.biocrick.com/Fostamatinib-R788-BCC5082.html
BioSynth	J-517972	https://www.biosynth.com/en/products/all-products/products/J-517972.html
Chem Scene	CS-2152	http://www.chemscene.com/901119-35-5.html
ChemMol	49401459	http://www.chemmol.com/chemmol/49401459.html
ChemMol	97301164	http://www.chemmol.com/chemmol/97301164.html
Chemspace	CSSB00015188362	https://chem-space.com/CSSB00015188362
Clearsynth	CS-DL-00637	https://www.clearsynth.com/en/CSDL00637.html
DC Chemicals	DC9841	http://www.dcchemicals.com/product_show-Fostamatinib_R788_.html
Excenen	EX-A108	http://www.excenen.com/searchresultlist.php?id=901119-35-5
Finetech	FT-0699180	http://www.finetechnology-ind.com/prod/detail/pub/901119-35-5.html
Hairui	HR114464	http://www.hairuichem.com/en/product/901119-35-5.html
Matrix Scientific	125210	https://www.matrixscientific.com/125210.html
MedChem Express	HY-13038A	https://www.medchemexpress.com/r788.html
Molcore	MC105510	https://www.molcore.com/product/901119-35-5
MuseChem	I005396	https://www.musechem.com/product/I005396.html
Renno Tech	RL05675	http://www.rennotech.com/product_show.asp?id=5923
Smolecule	S637386	https://www.smolecule.com/products/s637386
Sun-shine Chemical	R788	http://www.sun-shinechem.com/Details/R788/2069/901119-35-5.html
Synblock Inc	PB25570	http://www.synblock.com/product/901119-35-5.html
THE BioTek	bt-341464	https://www.thebiotek.com/product/others/bt-341464
Vesino Industrial Co Ltd	VA12036	http://www.vsnchem.com/goto/product/51359/
abcr GmbH	AB457968	http://www.abcr.com/shop/en/AB457968
eNovation Chemicals	D210852	https://www.enovationchem.com/ProductDetails.asp?ProductID=D210852
eNovation Chemicals	Y0974202	https://www.enovationchem.com/ProductDetails.asp?ProductID=Y0974202
iChemical	EBD29678	http://www.ichemical.com/chemicals/cas-901119-35-5

PubMed

Title	Date	PubMed

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.

Name

Type

Language

FOSTAMATINIB

Official 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-4-((PHOSPHONOOXY)METHYL)-

Systematic Name

English

R935788 FREE ACID

Code

English

Fostamatinib [WHO-DD]

Common Name

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 DIHYDROGEN PHOSPHATE

Systematic Name

English

R-788 FREE ACID

Code

English

R788 FREE ACID

Code

English

fostamatinib [INN]

Common Name

English

R-935788 FREE ACID

Code

English

FOSTAMATINIB [MI]

Common Name

English

FOSTAMATINIB [USAN]

Common Name

English

Classification Tree Code System Code

WHO-ATC

B02BX09