Deferasirox

Deferasirox

Systematic (IUPAC) name
4-[(3Z,5E)-3,5-bis(6-oxo-1-cyclohexa-2,4- dienylidene)-1,2,4-triazolidin-1-yl]benzoic acid
Clinical data
Licence data	EMA:Link, US FDA:link
Pregnancy category	AU: C US: B (No risk in non-human studies)
Legal status	UK: POM (Prescription only) US: ℞-only
Routes of administration	Oral
Pharmacokinetic data
Bioavailability	70%
Protein binding	99%
Metabolism	Hepatic glucuronidation
Biological half-life	8 to 16 hours
Excretion	Fecal (84%) and renal (8%)
Identifiers
CAS Number	201530-41-8 Y
ATC code	V03AC03 (WHO)
PubChem	CID: 5493381
DrugBank	DB01609 Y
ChemSpider	4591431 Y
UNII	V8G4MOF2V9 Y
KEGG	D03669 Y
ChEMBL	CHEMBL550348 N
Chemical data
Formula	C21H15N3O4
Molecular mass	373.362 g/mol
SMILES O=C4/C=C\C=C/C4=C2\N(N/C(=C1\C(=O)\C=C/C=C1)N2)c3ccc(C(=O)O)cc3
InChI InChI=1S/C21H15N3O4/c25-17-7-3-1-5-15(17)19-22-20(16-6-2-4-8-18(16)26)24(23-19)14-11-9-13(10-12-14)21(27)28/h1-12,22-23H,(H,27,28)/b19-15-,20-16+ Y Key:FMSOAWSKCWYLBB-VBGLAJCLSA-N Y
NY (what is this?)  (verify)

Deferasirox (marketed as Exjade, Desirox, Defrijet, Desifer...) is an oral iron chelator. Its main use is to reduce chronic iron overload in patients who are receiving long-term blood transfusions for conditions such as beta-thalassemia and other chronic anemias. It is the first oral medication approved in the USA for this purpose.

It was approved by the United States Food and Drug Administration (FDA) in November 2005. According to FDA (May 2007), renal failure and cytopenias have been reported in patients receiving deferasirox oral suspension tablets. It is approved in the European Union by the European Medicines Agency (EMA) for children 6 years and older for chronic iron overload from repeated blood transfusions.

Properties of deferasirox

Two deferasirox molecules binding iron

The half-life of deferasirox is between 8 and 16 hours allowing once a day dosing. Two molecules of deferasirox are capable of binding to 1 atom of iron which are subsequently eliminated by fecal excretion. Its low molecular weight and high lipophilicity allows the drug to be taken orally unlike deferoxamine which has to be administered by IV route (intravenous infusion). Together with deferiprone, deferasirox seems to be capable of removing iron from cells (cardiac myocytes and hepatocytes) as well as removing iron from the blood.

Synthesis

Deferasirox can be prepared from simple commercially available starting materials (salicylic acid, salicylamide and 4-hydrazinobenzoic acid) in the following two-step synthetic sequence:

The condensation of salicyloyl chloride (formed in situ from salicylic acid and thionyl chloride) with salicylamide under dehydrating reaction conditions results in formation of 2-(2-hydroxyphenyl)-1,3(4H)-benzoxazin-4-one. This intermediate is isolated and reacted with 4-hydrazinobenzoic acid in the presence of base to give 4-(3,5-bis(2-hydroxyphenyl)-1,2,4-triazol-1-yl)benzoic acid (Deferasirox).

Risks

Deferasirox was the #2 drug on the list of 'Most frequent suspected drugs in reported patient deaths' compiled by the Institute for Safe Medical Practices in 2009. There were 1320 deaths reported, perhaps explained by an update to the ADE data of Novartis, and a new boxed warning about gastrointestinal haemorrhage as well as kidney and liver failure.