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1. (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
2. 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)-
3. 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)-, Sodium Salt (1:2)
4. Fostamatinib Disodium
5. Fostamatinib Disodium Anhydrous
6. Fostamatinib Disodium Hydrate
7. Fostamatinib Disodium Salt Hexahydrate
8. R-788 Free Acid
9. R-788 Sodium
10. R-788 Sodium Anhydrous
11. R-788 Sodium Hydrate
12. R-935788 Free Acid
13. R-935788 Sodium Anhydrous
14. R-935788 Sodium Hydrate
15. R788 Free Acid
16. R788 Sodium
17. R788 Sodium Anhydrous
18. R788 Sodium Hydrate
19. R935788 Free Acid
20. R935788 Sodium Anhydrous
21. R935788 Sodium Hydrate
22. Tavalisse
1. 901119-35-5
2. R788
3. Fostamatinib (r788)
4. Tavalisse
5. R-788 Free Acid
6. R788 Free Acid
7. R-935788 Free Acid
8. [6-[[5-fluoro-2-(3,4,5-trimethoxyanilino)pyrimidin-4-yl]amino]-2,2-dimethyl-3-oxopyrido[3,2-b][1,4]oxazin-4-yl]methyl Dihydrogen Phosphate
9. Fostamatinib [usan]
10. Fostamatinib(r788)
11. R935788 Free Acid
12. R 788
13. R-788
14. Sq8a3s5101
15. R7935788
16. Fostamatinib (usan)
17. 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)-
18. Tavlesse
19. [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
20. R788 Compound
21. Fostamatinib [usan:inn]
22. Unii-sq8a3s5101
23. R-935788
24. (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
25. 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]-
26. R 788 Compound
27. R788 (fostamatinib)
28. Fostamatinib [mi]
29. Fostamatinib [inn]
30. Fostamatinib [who-dd]
31. Gtpl7796
32. Schembl1201371
33. Chembl2103830
34. Ex-a108
35. Bcpp000226
36. Dtxsid401009170
37. Hms3651h09
38. Bcp01871
39. Bdbm50431381
40. Hy-13038a
41. Mfcd16628163
42. Nsc800102
43. S2625
44. Zinc43131420
45. Akos025404920
46. Am81257
47. Bcp9000704
48. Ccg-270128
49. Db12010
50. Nsc-800102
51. Pb25570
52. Ncgc00346622-01
53. Ncgc00346622-02
54. [6-[[5-fluoro-2-(3,4,5-trimethoxyanilino)pyrimidin-4-yl]amino]-2,2-dimethyl-3-oxo-pyrido[3,2-b][1,4]oxazin-4-yl]methyl Dihydrogen Phosphate
55. Ac-30126
56. As-56399
57. Ft-0699180
58. Sw219234-1
59. D09347
60. A857764
61. J-517972
62. Q5473550
63. R788;r7935788;r 788;r 7935788;r-788;r-7935788
64. (6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-3-oxo-2h-pyrido[3,2-b][1,4]oxazin-4(3h)-yl)methyl Dihydrogen Phosphate
65. (6-(5-fluoro-2-(3,4,5-trimethoxyphenylamino)pyrimidin-4-ylamino)-2,2-dimethyl-3-oxo-2,3-dihydropyrido[3,2-b][1,4]oxazin-4-yl)methyl Dihydrogen Phosphate
66. [6-[[5-fluoro-2-[(3,4,5-trimethoxyphenyl)amino]pyrimidin-4-yl]amino]-2,2-dimethyl-3-oxopyrido[2,3-e][1,4]oxazin-4-yl]methyl Dihydrogen Phosphate
67. 2rc
68. 6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)-4-pyrimidinyl)amino)-2,2-dimethyl-4-((phosphonooxy)methyl)-2h-pyrido(3,2-b)-1,4-oxazi N-3(4h)-one
69. 6-[[5-fluoro-2-[(3,4,5-trimethoxyphenyl)amino]-4-pyrimidinyl]amino]-2,2-dimethyl-4-[(phosphonooxy)methyl]-2h-pyrido[3,2-b]-1,4-oxazin-3(4h)-one
70. R 788; 6-[[5-fluoro-2-[(3,4,5-trimethoxyphenyl)amino]-4-pyrimidinyl]amino]-2,2-dimethyl-4-[(phosphonooxy)methyl]-2h-pyrido[3,2-b]-1,4-oxazin-3(4h)-one
| Molecular Weight | 580.5 g/mol |
|---|---|
| Molecular Formula | C23H26FN6O9P |
| XLogP3 | 1.6 |
| Hydrogen Bond Donor Count | 4 |
| Hydrogen Bond Acceptor Count | 15 |
| Rotatable Bond Count | 10 |
| Exact Mass | 580.14829159 g/mol |
| Monoisotopic Mass | 580.14829159 g/mol |
| Topological Polar Surface Area | 187 Ų |
| Heavy Atom Count | 40 |
| Formal Charge | 0 |
| Complexity | 904 |
| Isotope Atom Count | 0 |
| Defined Atom Stereocenter Count | 0 |
| Undefined Atom Stereocenter Count | 0 |
| Defined Bond Stereocenter Count | 0 |
| Undefined Bond Stereocenter Count | 0 |
| Covalently Bonded Unit Count | 1 |
Fostamatinib is indicated for use in the treatment of chronic immune thrombocytopenia (ITP) in patients who have had insufficient response to previous therapy.
FDA Label
Tavlesse is indicated for the treatment of chronic immune thrombocytopenia (ITP) in adult patients who are refractory to other treatments.
Treatment of idiopathic thrombocytopenic purpura as a model for immunomodulation
Treatment of chronic idiopathic arthritis (including rheumatoid arthritis , ankylosing spondylarthritis , psoriatic arthritis and juvenile idiopathic arthritis )
The active metabolite of fostamatinib, R406, inhibits signal transduction by Fc receptors involved in the antibody-mediated destruction of platelets by immune cells in chronic ITP. This results in increased platelet counts in this population. R406 produces inhibition of T and B lymphocyte activation by T-cell receptors (TCRs) and B-cell receptors (BCRs) respectively. It can also inhibit signalling via Fc receptors which could have applications in treating allergic symptoms through prevention of mast cell degranulation. Inhibition of Fc receptor signalling system also affected by R406 suppresses both dendritic cell maturation and antigen presentation and may contribute to the effects of fostamatinib. As a knock-on effect of disabling signal transduction from Fc receptors, TCRs, and BCRs, the production of inflammatory mediators and cytokines like tumour necrosis factor , leukotriene C4, interleukin-8, and granulocyte-macrophage colony-stimulating factor. Fostamatinib can produce hypertension through off-target effects
B02BX
B - Blood and blood forming organs
B02 - Antihemorrhagics
B02B - Vitamin k and other hemostatics
B02BX - Other systemic hemostatics
B02BX09 - Fostamatinib
Absorption
Fostmatinib is the methylene phosphate prodrug of R406, the active metabolite. It is extensively hydrolyzed by intestinal alkaline phosphatase. Only negligible amounts of fostamatinib enter systemic circulation. R406 has an absolute bioavailability of 55% and reaches peak plasma concentrations in approximately 1.5 h. Administration with a high calorie, high fat meal increases exposure by 23% and the maximum plasma concentration by 15%. This may lengthen time to peak plasma concentration to approximately 3 h. Exposure to R406 is known to be dose proportional up to 200 mg twice daily. R406 accumulates 2-3 fold with twice daily dosing at 100-160 mg.
Route of Elimination
About 80% of R406 is excreted in the feces, primarily as the O-glucuronide conjugate and the O-desmethyl metabolite produced by gut bacteria. The remaining 20% is excreted in the urine as the N-glucuronide conjugate.
Volume of Distribution
R406 has an apparent oral volume of distribution of approximately 400 L.
Clearance
R406 has an apparent oral clearance of approximately 300 mL/min.
Fostamatinib is metabolized in the gut by alkaline phosphatase to the active metabolite R406. R406 is further oxidized by CYP3A4 and glucuronidated by UGT1A9. Plasma metabolites found include an O-glucuronide conjugate, an N-glucuronide conjugate, an O-desmethyl metabolite, and a sulfate conjugate. A 3,5 benzene diol metabolite forms in the feces via processing of the O-desmethyl metabolite by gut bacteria.
R406 has a half-life of elimination of approximately 15 h.
The active metabolite of fostamatinib, R406, is an inhibitor of spleen tyrosine kinase (Syk). It binds reversibly to the ATP binding pocket with high affinity (Ki = 30nM), inhibiting the kinase activity with an IC50 of 41nM. Syk is a cytosolic protein kinase and part of the signalling cascade which occurs with Fc receptors, TCRs, and BCRs. It contains two src homology 2 (SH2) domains separated by a linker domain. These SH2 domains bind to tyrosine residues on the immunoreceptor tyrosine-based activating motif phosphorylated by Lyn, another kinase in the cascade. This motif is located on the cytoplasmic regions of several immune receptors including Fc receptors, TCRs, BCRs, and natural killer cell receptors. The flexibility provided by the linker enables the protein to bind to many receptor types. Inhibition of Syk suppresses downstream signal transduction. While Syk plays a role in some pathways involved in the generation of the oxidative burst by neutrophils or phagocytosis by macrophages, R406 does not have a significant effect on these processes. This is likely due to redundant pathways which do not involve Syk. Similarly Syk does not produce significant effects on platelet activation despite its involvement in glycoprotein IV and integrin based signalling. Activation of antibody-dependent cell-mediated toxicity by natural killer cells is also unaffected despite the involvement of Syk in Fc receptor signalling. R406 binds to the adenosine A3 receptor as an antagonist as well as the adenosine and monoamine uptake transporters as an inhibitor. It has also been found to be an inhibitor of UDP glucuronosyltransferase UGT1A1, phosphodiesterase PDE5, fatty acid amide hydrolase, 5-lipoxygenase, cathepsin L, and cathepsin S. R406 appears to inhibit a wide range of kinases at higher concentrations. It is thought that inhibition of some of these targets may be responsible for the increase in blood pressure seen with fostamatinib.
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