Ximelagatran

Ximelagatran

Systematic (IUPAC) name
ethyl 2-[[(1R)-1-cyclohexyl-2- [(2S)-2-[[4-(N'-hydroxycarbamimidoyl) phenyl]methylcarbamoyl]azetidin-1-yl]- 2-oxo-ethyl]amino]acetate
Clinical data
Pregnancy category	uncategorised
Legal status	Rx only/POM
Routes of administration	Oral
Pharmacokinetic data
Bioavailability	20%
Metabolism	None
Biological half-life	3-5h
Excretion	Renal (80%)
Identifiers
CAS Number	192939-46-1 N
ATC code	B01AE05 (WHO)
PubChem	CID: 9574101
IUPHAR/BPS	6381
DrugBank	DB04898 Y
ChemSpider	7848559 Y
UNII	49HFB70472 Y
KEGG	D01981 Y
ChEMBL	CHEMBL522038 Y
Chemical data
Formula	C24H35N5O5
Molecular mass	473.57 g·mol−1 (429 g/mol after conversion)
SMILES O=C(NCc1ccc(C(=N\O)\N)cc1)[C@H]3N(C(=O)[C@H](NCC(=O)OCC)C2CCCCC2)CC3
InChI InChI=1S/C24H35N5O5/c1-2-34-20(30)15-26-21(17-6-4-3-5-7-17)24(32)29-13-12-19(29)23(31)27-14-16-8-10-18(11-9-16)22(25)28-33/h8-11,17,19,21,26,33H,2-7,12-15H2,1H3,(H2,25,28)(H,27,31)/t19-,21+/m0/s1 Y Key:ZXIBCJHYVWYIKI-PZJWPPBQSA-N Y
NY (what is this?)  (verify)

Ximelagatran (Exanta or Exarta, H 376/95) is an anticoagulant that has been investigated extensively as a replacement for warfarin that would overcome the problematic dietary, drug interaction, and monitoring issues associated with warfarin therapy. In 2006, its manufacturer AstraZeneca announced that it would withdraw pending applications for marketing approval after reports of hepatotoxicity (liver damage) during trials, and discontinue its distribution in countries where the drug had been approved (Germany, Portugal, Sweden, Finland, Norway, Iceland, Austria, Denmark, France, Switzerland, Argentina and Brazil).

Method of action

Ximelagatran, a direct thrombin inhibitor, was the first member of this class that can be taken orally. It acts solely by inhibiting the actions of thrombin. It is taken orally twice daily, and rapidly absorbed by the small intestine. Ximelagatran is a prodrug, being converted in vivo to the active agent melagatran. This conversion takes place in the liver and many other tissues through dealkylation and dehydroxylation (replacing the ethyl and hydroxyl groups with hydrogen).

Uses

Ximelagatran was expected to replace warfarin and sometimes aspirin and heparin in many therapeutic settings, including deep venous thrombosis, prevention of secondary venous thromboembolism and complications of atrial fibrillation such as stroke. The efficacy of ximelagatran for these indications had been well documented, except for non valvular atrial fibrillation.

An advantage, according to early reports by its manufacturer, was that it could be taken orally without any monitoring of its anticoagulant properties. This would have set it apart from warfarin and heparin, which require monitoring of the international normalized ratio (INR) and the partial thromboplastin time (PTT), respectively. A disadvantage recognised early was the absence of an antidote in case acute bleeding develops, while warfarin can be antagonised by vitamin K and heparin by protamine sulfate.

Side-effects

Ximelagatran was generally well tolerated in the trial populations, but a small proportion (5-6%) developed elevated liver enzyme levels, which prompted the FDA to reject an initial application for approval in 2004. The further development was discontinued in 2006 after it turned out hepatic damage could develop in the period subsequent to withdrawal of the drug. According to AstraZeneca, a chemically different but pharmacologically similar substance, AZD0837, is undergoing testing for similar indications.

Melagatran synthesis

Sobrera, L. A.; Castaner, J.; Drugs Future, 2002, 27, 201.